Compounds and methods for the treatment of ocular disorders

ABSTRACT

Described herein are compositions and methods for the treatment of ocular surface disorders including meibomian gland dysfunction, blepharitis, dry eye disease and other inflammatory and/or infectious disease of the anterior surface of the eye. Said compositions and methods comprise keratolytic conjugates which demonstrate keratolytic activity, and anti-inflammatory or other desirable activities. Topical administration of said compositions to the eyelid margin or surrounding areas provides therapeutic benefit to patients suffering from ocular surface disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of InternationalApplication No. PCT/IB2020/000288, filed Apr. 16, 2020, and claims thebenefit of U.S. Provisional Application No. 62/835,963, filed Apr. 18,2019, all of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

Restasis (0.05% cyclosporine A, Allergan) was approved by the Food andDrug Administration (FDA) to increase tear production in patients whosetear production is presumed to be suppressed due to ocular inflammationassociated with keratoconjunctivitis sicca. Xiidra® (lifitegrastophthalmic solution) 5% is indicated for the treatment of signs andsymptoms of dry eye disease (DED).

SUMMARY OF THE INVENTION

Provided in certain embodiments herein are compounds, pharmaceutical(e.g., ophthalmic) compositions, and methods of treatment. In specificembodiments, methods of treatment provided herein include the treatmentof ocular and/or periocular indications or abnormalities. In someembodiments, the ocular and/or periocular indications or abnormalitiestreated by or with a composition or compound provided herein areindications or abnormalities that have multifactorial etiologies and/orinteractions. In certain embodiments provided herein are compounds (andcompositions comprising such compounds) that have multifunctionalefficacies, such as when administered in or around the eye (e.g., to theocular surface, the eyelid, such as the eyelid margin or the innersurface of the eyelid, or the like).

In certain embodiments, methods provided herein involve the method oftreating meibomian gland dysfunction (MGD).

Currently there are no approved pharmacological agents useful for thetreatment of MGD. The recognition that terminal duct obstruction fromhyperkeratinization of the ductal epithelium on meibomian glands is acore mechanism behind meibomian gland dysfunction (MGD) is consistentwith clinical experience demonstrating that effective treatments for MGDrequire resolution of ductal obstruction and evacuation of glandularcontents (Nichols et al, 2011; Lane et al, 2012; Blackie et al, 2015).Warm compresses and thermal/mechanical devises (e.g., LipiFlow) are usedin an attempt to raise the internal temperature of the meibomian glandsover the normal melting point for meibum (i.e., 32° C. to 40° C.) in anattempt to resolve terminal duct obstruction (Lane et al, 2012).Unfortunately, warm compresses are unable to achieve this benefit forseverely obstructed glands which can having a melting point >40° C.Current technology for removing keratinized obstruction of the meibomiangland also includes physical removal methods (e.g., debridement andgland probing), which are quite painful to patients.

Subsequent to a period of MGD, various stages of inflammatory orbacterial disease at the ocular surface are frequently observed becausemeibomian gland obstruction can cause a cascade of events that includefurther deterioration of the glands (Knop, IOVS, 2011) from stasis ofthe meibum in the secretory glands, mechanical pressure and stress fromglandular obstruction, and increased bacterial growth that is associatedwith the downstream release of bacterial lipases, toxic mediators,and/or inflammatory mediators. All these factors reduce the qualityand/or quantity of meibum the glands can release which in turn can causechronic mechanical traumatization of the conjunctival, corneal andeyelid tissues which will lead to further tissue damage and the releaseof inflammatory mediators. Thus, many patients suffering from MGD alsohave inflammatory disease affecting their conjunctiva, cornea, larcrimalgland, lids or goblet cells causing comorbid conditions such as dry eyesyndrome or blepharitis for which there is an unmet medical need.

For example, literature has used the terms posterior blepharitis and MGDas if they were synonymous, but these terms are not interchangeable.Posterior blepharitis describes inflammatory conditions of the posteriorlid margin, of which MGD is only one possible cause. In its earlieststages, MGD may not be associated with clinical signs characteristic ofposterior blepharitis. At this stage, affected individuals may besymptomatic, but alternatively, they may be asymptomatic and thecondition regarded as subclinical. As MGD progresses, symptoms developand lid margin signs, such as changes in meibum expressibility andquality and lid margin redness, may become more visible. At this point,an MGD-related posterior blepharitis is said to be present.

In certain embodiments, provided herein are methods of treating ocular(or dermatological) disorders associated with keratosis (e.g., lidkeratosis, surface ocular keratosis, and/or gland blockage—such as inMGD), microbial infiltration/infection (e.g., bacterialinfiltration/infection), and/or inflammation (such as inflammationassociated keratosis or not associated with keratosis). In certaininstances, disorders of the skin and/or eye (and/or surroundtissue/skin) are difficult to differentially diagnose and/or havemultiple etiologies. For example, in some instances, it can be difficultto distinguish between ocular disorders that involve (1) inflammationonly, (2) inflammation associated with keratolytic activity, (3)inflammation associated with both keratolytic activity (e.g., inducingkeratosis) and microbial infiltration, (4) keratolytic activity, but notinflammation and/or microbial infiltration, or various othercombinations. In some instances, compounds and compositions providedherein can be used in such ocular and/or dermatological indicationswithout the need for differential diagnosis (which can be difficult,e.g., because of similar symptom scores, etc.). Further, many ocularand/or dermatological disorders involve multiple etiologies, suchinflammation, microbial infiltration, keratolytic activity, or variouscombinations thereof. As a result, therapeutic agents, such as thosedescribed herein, that target multiple etiologies are beneficial inproviding therapeutic efficacy, such as by targeting both an underlyingcondition (e.g., keratolytic activity and/or microbial infiltration) anda symptom, such as inflammation or dry eye.

As such, provided herein are compounds, compositions, methods, andformulations for the treatment of ocular (e.g., periocular) ordermatological disorders, such as those having abnormalities havingmultifactorial etiologies. In specific embodiments, ocular disordersinclude, by way of non-limiting example, surface disorders, such as MGD,dry eye and associated inflammatory and bacterial disease.

In certain embodiments, provided herein are compounds having thestructure of Formula (Ia):

wherein

R¹ is aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein the aryl,cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted;

R², R³, and R⁴ are each independently H, cyano, halo, ester, alkoxy,alkyl, heteroalkyl, cycloalkyl or heterocyclyl, wherein the alkoxy,alkyl, heteroalkyl, cycloalkyl or heterocyclyl is optionallysubstituted;

R⁵ is -L-R^(5a), wherein L is a bond, alkyl, or heteroalkyl, and R^(5a)is absent, a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl,wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl isoptionally substituted;

R⁶ is H, alkyl, or heteroalkyl;

each R⁷ is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl,cycloalkyl or haloalkyl;

n is 0-6;

R is -L′-D, wherein:

D is a keratolytic agent (e.g., radical thereof); and

L′ is a linker,

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, L′ comprises one or more linker groups, each linkergroup being selected from the group consisting of a bond, —O—, —S—,halo, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), disulfide,ester, and carbonyl (>C═O). In some embodiments, each linker group isselected from the group consisting of a bond, —O—, —S—, halo, alkyl(alkylenyl), heteroalkyl (heteroalkylenyl), and ester. In someembodiments, each linker group is selected from alkyl (alkylene) andheteroalkyl (heteroalkylene), the alkyl (alkylene) or heteroalkyl(heteroalkylene) being optionally substituted. In some embodiments, L′is alkyl (alkylene) substituted with oxo and one or more of alkyl andheteroalkyl. In some embodiments, the alkyl or heteroalkyl issubstituted with one or more halo, alkyl, or haloalkyl. In someembodiments, the alkyl or heteroalkyl is substituted with one or morealkyl or haloalkyl. In some embodiments, L′ is a bond, —O—, —S—, halo,(C═O), —(C═O)alkyl-, —(C═O)heteroalkyl-, —(C═O)O—, —(C═O)Oalkyl-,—(C═O)Oheteroalkyl-, —(C═O)S—, —(C═O)Salkyl-, —(C═O)Sheteroalkyl-,alkylene, or heteroalkylene, where each alkyl, heteroalkyl, alkylene, orheteroalkyl is optionally substituted. In some embodiments, L′ is (C═O),—(C═O)alkyl-, —(C═O)heteroalkyl-, —(C═O)O—, —(C═O)Oalkyl-,—(C═O)Oheteroalkyl-, —(C═O)S—, —(C═O)Salkyl-, —(C═O)Sheteroalkyl-,alkylene, or heteroalkylene.

In some embodiments, the linker comprises the structure of Formula (A):

wherein:

Z is a bond, —O—, —S—, or optionally substituted amino;

G¹ and G² are each independently hydrogen, halo, alkyl, heteroalkyl, orcycloalkyl, wherein

the alkyl or cycloalkyl is optionally substituted; and

g is 1-20.

In some embodiments, the compound comprises more than one linker ofFormula (A). In some embodiments, Z is a bond or —O—. In someembodiments, Z is a bond and G¹ and G² are each independently hydrogen,alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl are optionallysubstituted. In some embodiments, Z is —O— and G¹ and G² are eachindependently hydrogen, alkyl, or cycloalkyl, wherein the alkyl orcycloalkyl are optionally substituted. In some embodiments, Z is a bondor —O— and G¹ is hydrogen and G² is alkyl or haloalkyl. In someembodiments, Z is a bond or —O— and G¹ is hydrogen and G² is methyl. Insome embodiments, Z is a bond or —O— and G¹ and G² are eachindependently hydrogen. In some embodiments, Z is a bond and G¹ ishydrogen and G² is methyl. In some embodiments, Z is a bond and G¹ andG² are each independently hydrogen. In some embodiments, Z is —O—, G¹ ishydrogen and G² is methyl. In some embodiments, Z is —O— and G¹ and G²are each independently hydrogen.

In some embodiments, g is 1-20. In some embodiments, g is 1-10. In someembodiments, g is 1-5. In some embodiments, g is 2. In some embodiments,g is 1.

In some embodiments, g is 1 or 2, Z is a bond and G¹ is hydrogen, and G²is methyl. In some embodiments, g is 1 or 2, Z is a bond, and G¹ and G²are each independently hydrogen. In some embodiments, g is 1 or 2, Z is—O—, G¹ is hydrogen, and G² is methyl. In some embodiments, g is 1 or 2,Z is —O—, and G¹ and G² are each independently hydrogen.

In some embodiments, the linker is selected from one or more of thegroup consisting of a bond, —O—, methylene,

In some embodiments, the linker is a bond, methylene,

In some embodiments, D is selected from alkyl and heteroalkyl, the alkylor heteroalkyl being optionally substituted. In some embodiments, D isalkyl substituted with oxo and one or more of the group selected fromsubstituted alkyl and substituted heteroalkyl. In some embodiments, thealkyl is substituted with one or more of the group selected from —SH,—OH, substituted or unsubstituted aryl, substituted or unsubstitutedheteroalkyl, or substituted or unsubstituted heterocycloalkyl. In someembodiments, D is heteroalkyl substituted with oxo and one or more ofthe group selected from substituted alkyl and substituted heteroalkyl.In some embodiments, the heteoralkyl is substituted with one or more ofthe group selected from —SH, —OH, or substituted or unsubstitutedheteroalkyl. In some embodiments, the heteroalkyl is substituted withone or more of the group selected from —SH, —OH, alkyl, (C═O)alkyl,(C═O)heteroalkyl, and —NH(C═O)alkyl.

In some embodiments, D is selected from one or more of the groupconsisting of —CH₂OH, —CH(CH₃)OH, —CH₂(OCH₂CH₂)₄OH, —CH₂CH₂(OCH₂CH₂)₄OH,

In some embodiments, D is —CH₂OH, —CH(CH₃)OH, —CH₂(OCH₂CH₂)₄OH,—CH₂CH₂(OCH₂CH₂)₄OH,

In some embodiments, D is

In some embodiments, D is

In some embodiments, D or the keratolytic agent is

In some embodiments, D is a“keratolytic agent” radical that, uponrelease, hydrolysis, or other mechanism metabolizes or otherwiseproduces (e.g., when administered to an individual or patient, such asin or around the eye, such as the eyelid margin) an active keratolyticagent. In some instances, upon release (e.g., by hydrolysis or othermechanism), D produces a plurality of active keratolytic agents. In someinstances, the active keratolytic agent comprises one or more of —SH,—OH, COOH (or COO—), or disulfide. In some embodiments, the activekeratolytic agent is a carboxylic acid. In some embodiments, the activekeratolytic agent is selected from the group consisting of acetic acid,glycolic acid, lactic acid, lipoic acid, pivalic acid, isobutryic acid,butyric acid, propionic acid, formic acid, and carbonic acid. In someembodiments, the active keratolytic agent is a thiol.

In some embodiments, L is attached to D by a bond.

In certain instances, combination of an anti-inflammatory and/oranti-microbial moiety (e.g., having a structure of any formula providedherein, minus the R′) with a keratolytic moiety (e.g., being representedby and/or having a structure of D). In certain embodiments, suchmoieties are radicals connected by a linker that is a bond, with thekeratolytic moiety being hydrolyzable to produce both (1) ananti-inflammatory and/or anti-microbial agent and (2) one or more activekeratolytic agent. In some embodiments, such moieties are radicalsconnected by a hydrolyzable linker, with the hydrolyzable linker beinghydrolyzable, such that both (1) an anti-inflammatory and/oranti-microbial agent and (2) one or more active keratolytic agent arereleased (e.g., in vivo, such as after therapeutic (e.g., topical)delivery to the eye and/or skin).

In certain embodiments, provided herein are compounds having thestructure of Formula (Ia):

wherein

R¹ is aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein the aryl,cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted;

R², R³, and R⁴ are each independently H, cyano, halo, ester, alkoxy,alkyl, heteroalkyl, cycloalkyl or, heterocyclyl, wherein the alkoxy,alkyl, heteroalkyl, cycloalkyl or, heterocyclyl is optionallysubstituted;

R⁵ is -L-R^(5a), wherein L is a bond, alkyl, or heteroalkyl, and R^(5a)is absent, a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl,wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl isoptionally substituted;

R⁶ is H, alkyl, or heteroalkyl;

each R⁷ is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl,cycloalkyl, or haloalkyl;

n is 0-6; and

R is alkyl or heteroalkyl substituted with at least one oxo, and furtheroptionally substituted,

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, R¹ is optionally substituted aryl, heteroaryl,cycloalkyl, or heterocyclyl. In some embodiments, R¹ is optionallysubstituted aryl or heteroaryl. In some embodiments, R¹ is heteroaryl.In some embodiments, R¹ is benzofuran. In some embodiments, R¹ is

In some embodiments, R² and R⁴ are each independently H, halo, alkoxy,or alkyl. In some embodiments, R² and R⁴ are each independently H, halo,or alkyl. In some embodiments, R² and R⁴ are halo. In some embodiments,R² and R⁴ are each independently chloro. In some embodiments, R³ is H,alkyl, halo, heteroalkyl, or cycloalkyl. In some embodiments, R³ is H,alkyl, or halo. In some embodiments, R³ is H. In some embodiments, R²and R⁴ are each independently chloro and R³ is H.

In some embodiments, L is a bond. In some embodiments, L is a bond andR^(5a) is an optionally substituted aryl or heteroaryl. In someembodiments, L is alkyl and R^(5a) is absent. In some embodiments, L isalkyl and R^(5a) is optionally substituted aryl or optionallysubstituted heteroaryl. In some embodiments, R⁵ is optionallysubstituted aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl. In someembodiments, R⁵ is optionally substituted aryl-alkyl orheteroaryl-alkyl. In some embodiments, R⁵ is substituted aryl-alkyl orheteroaryl-alkyl. In some embodiments, R⁵ is substituted aryl-alkyl. Insome embodiments, R⁵ is a sulfonyl substituted aryl-alkyl. In someembodiments, R⁵ is a monosulfonyl substituted aryl-alkyl. In someembodiments, the sulfonyl substituent is methyl sulfone. In someembodiments, R⁵ is

In some embodiments, R⁶ is heteroalkyl. In some embodiments, R⁶ is—(C═O)alkyl or —(C═O)heteroalkyl. In some embodiments, R⁶ is alkyl. Insome embodiments, R⁶ is H.

In some embodiments, each R⁷ is independently H, halo, alkyl,heteroalkyl, or cycloalkyl. In some embodiments, each R⁷ isindependently H, halo, or alkyl. In some embodiments, n is 1 and R⁷ ishalo or alkyl. In some embodiments, n is 2 and R⁷ is independently haloor alkyl. In some embodiments, n is 0.

In some embodiments, R¹ is heteroaryl, R² and R⁴ are each independentlyhalo, and R⁵ is a substituted aryl-alkyl. In some embodiments, R¹ isheteroaryl, R² and R⁴ are each independently halo, R³ is H, R⁵ is asubstituted aryl-alkyl, R⁶ is H or alkyl, and n is 0. In someembodiments, R¹ is benzofuran, R² and R⁴ are each independently halo, R³is H, R⁵ is a sulfonyl substituted aryl-alkyl, R⁶ is H, and n is 0. Insome embodiments, R¹ is benzofuran, R² and R⁴ are each chloro, R³ is H,R⁵ is a sulfonyl mono-substituted aryl-alkyl, R⁶ is H, and n is 0. Insome embodiments, R¹ is:

R² and R⁴ are each chloro, R³ is H, R⁵ is:

R⁶ is H, and n is 0.

In some embodiments, the compound has the structure of Formula (Ib):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the alkyl or heteroalkyl of R is substituted withone or more substituent, each substituent independently selected fromthe group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether,disulfide, seleno, selenol, selenide, diselenide, sulfone, amide, halo,oxo, heterocyclyl, and cycloalkyl, wherein the heterocyclyl, andcycloalkyl is optionally substituted (e.g., with one or more substituentselected from the group consisting of alkyl, heteroalkyl, hydroxyl,thiol, thioether, disulfide, selenol, selenide, diselenide, sulfone,amide, halo and oxo). In some embodiments, the alkyl of R is substitutedwith one or more substituent, each substituent independently selectedfrom alkyl, oxo, heteroalkyl, haloalkyl, hydroxyl, thiol, thioether,disulfide, and heterocycloalkyl.

In some embodiments, R is:

X is —O— or a bond;

R⁸ is hydrogen, alkyl, heteroalkyl, or haloalkyl;

R⁹ is alkyl or heteroalkyl, the alkyl or heteroalkyl being optionallysubstituted,

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, X is —O— and R⁸ is alkyl or haloalkyl. In someembodiments, X is —O— and R⁸ is alkyl. In some embodiments, X is —O— andR⁸ is methyl. In some embodiments, X is a bond and R⁸ is alkyl orhaloalkyl. In some embodiments, X is a bond and R⁸ is alkyl. In someembodiments, X is a bond and R⁸ is methyl.

In some embodiments, the compound has the structure of Formula (Ic):

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, X is a bond. In some embodiments X is —O—. In someembodiments, X is a bond or —O— and the alkyl or heteroalkyl of R⁹ issubstituted with one or more substituent, each substituent independentlyselected from the group consisting of alkyl, heteroalkyl, hydroxyl,thiol, thioether, disulfide, seleno, selenol, selenide, diselenide,sulfone, amide, ester, carboxylic acid, halo, oxo, heterocyclyl, andcycloalkyl, wherein the heterocyclyl, and cycloalkyl is optionallysubstituted (e.g., with one or more substituent selected from the groupconsisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide,selenol, sulfone, amide, ester halo and oxo). In some embodiments, thealkyl or heteroalkyl of R⁹ is substituted with one or more substituent,each substituent independently selected from the group consisting ofalkyl, heteroalkyl, hydroxyl, thiol, thioether, disulfide, ester, oxo,and heterocyclyl.

In some embodiments, X is —O— and R⁹ is C₁₋₆ alkyl,—(CR^(d)R^(e))_(p)(C═O)O(C₁-C₆-alkyl), —(CR^(d)R^(e))_(p)carbocyclyl,—(CR^(d)R^(e))_(p)heterocyclyl, or

and

R^(d) and R^(e) are each independently H, halo, alkyl, alkoxy, hydroxyl,thioether, sulfide, thiol, disulfide, seleno, heteroalkyl, carbocyclyl,carbocyclylalkyl, carbocyclylalkoxy, carboxyl, heterocyclyl,heterocyclylalkyl, or heterocyclylalkoxy;

R¹⁰ is H, —(C═O)C₁₋₆ alkyl, or each R¹⁰ combines to form an optionallysubstituted heterocycloalkyl;

p is 1 to 6; and

wherein C₁₋₆ alkyl is optionally substituted with halo, alkyl,heteroalkyl, alkoxy, hydroxyl, thiol, disulfide, selenide, diselenide,amide, heterocyclyl or heterocyclylalkyl.

In some embodiments, X is —O— and R⁹ is C₁₋₆ alkyl. In some embodiments,the C₁₋₆ alkyl is optionally substituted with alkyl, heteroalkyl,alkoxy, hydroxyl, heterocyclyl, or heterocyclylalkyl.

In some embodiments, X is —O— and R⁹ is

In some embodiments, each R¹⁰ is independently hydrogen or —(C═O)C₁₋₆alkyl. In some embodiments, each R¹⁰ is hydrogen. In some embodiments,each R¹⁰ is —(C═O)C₁₋₆ alkyl. In some embodiments, the alkyl of—(C═O)C₁₋₆ alkyl is methyl, ethyl, propyl, isopropyl, or tert-butyl. Insome embodiments, the alkyl of —(C═O)C₁₋₆ alkyl is methyl. In someembodiments, the alkyl of —(C═O)C₁₋₆ alkyl is ethyl. In someembodiments, the alkyl of —(C═O)C₁₋₆ alkyl is propyl. In someembodiments, the alkyl of —(C═O)C₁₋₆ alkyl is isopropyl. In someembodiments, the alkyl of —(C═O)C₁₋₆ alkyl is tert-butyl.

In some embodiments, each R¹⁰ are taken together to form an optionallysubstituted heterocycloalkyl. In some embodiments, each R^(d) and R^(e)is independently hydrogen, halo, or alkyl. In some embodiments, eachR^(d) and R^(e) is hydrogen. In some embodiments, p is 1-5. In someembodiments, p is 1-3. In some embodiments, p is 1 or 2. In someembodiments, p is 1. In some embodiments, the heterocycloalkyl is2,2-dimethyl-1,3-dioxane, 2-methyl-1,3-dioxane, or 1,3-dioxane.

In some embodiments, X is a bond and R⁹ is C₁₋₆ alkyl, heteroalkyl orheterocyclylalkyl, wherein the C₁₋₆ alkyl may be linear or branched andis optionally substituted with halo, alkyl, heteroalkyl, alkoxyhydroxyl, thiol, disulfide, selenide, diselenide, amide, heterocyclyl orheterocyclylalkyl. In some embodiments, X is a bond and R⁹ isheteroalkyl. In some embodiments, X is a bond and the heteroalkyl is—(C═O)alkyl, wherein the alkyl is optionally substituted with —OH orheterocycloalkyl. In some embodiments, the heterocycloalkyl is adithiolane.

In some embodiments, X is bond or —O— and R⁹ is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

In some embodiments, X is a bond and R⁹ is —CH₂OH, —CH(CH₃)OH,—CH₂(OCH₂CH₂)₄OH, —CH₂CH₂(OCH₂CH₂)₄OH

In some embodiments, X is —O— and R⁹ is

In some embodiments, R⁹ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, CH₂OH,

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (I):

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (I′):

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (II):

One embodiment provides a pharmaceutical composition comprising anycompound provided herein, such as a compound of any one of Formula (Ia),Formula (Ib), Formula (Ic), Formula (I), Formula (I′), or Formula (II),or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient. Another embodiment provides thepharmaceutical composition, wherein the pharmaceutical composition issuitable for ophthalmic administration. Another embodiment provides thepharmaceutical composition, wherein the pharmaceutical composition issuitable for topical ophthalmic administration. In some embodiments,topical ophthalmic administration is administration in and/or around theeye, such as to the eyelid margin. In some embodiments, topicalophthalmic administration is administration to the ocular surface andthe inner surface to the eyelid.

In some embodiments, a compound or a pharmaceutical compositioncomprising any compound provided herein, such as a compound of any oneof Formula (Ia), Formula (Ib), Formula (Ic), Formula (I), Formula (I′),or Formula (II), or a pharmaceutically acceptable salt thereof, issubstantially hydrolytically stable (e.g., stable in an aqueouscomposition (e.g., solution), such as a buffer solution orophthalmically acceptable aqueous composition). In some embodiments, thecompound or the pharmaceutical composition is formulated in an aqueousvehicle. In some embodiments, the compound or the pharmaceuticalcomposition is formulated and stored in an aqueous vehicle. In someinstances, compositions or formulations provided herein are chemicallyand/or physically stable in an aqueous composition.

In some embodiments, a compound provided herein, such as a compound ofany one of Formula (Ia), Formula (Ib), Formula (Ic), Formula (I),Formula (I′), or Formula (II), or a pharmaceutically acceptable saltthereof, is hydrolyzed to an active pharmaceutical agent (e.g., a freeform of a radical of Formula (Ia), Formula (Ib), Formula (Ic), Formula(I), Formula (I′), or Formula (II), such as wherein R is a negativecharge or H) and a keratolytic agent. In some embodiments, the compoundor pharmaceutical composition is hydrolyzed to an active pharmaceuticalagent and a keratolytic agent in an ocular space. In some embodiments,the compound or pharmaceutical composition is hydrolyzed to an activepharmaceutical agent and a keratolytic agent by an esterase in an ocularspace. In some embodiments, the active pharmaceutical agent is ananti-inflammatory agent. In some embodiments the anti-inflammatory agentis lifitegrast. In some embodiments, the keratolytic agent is acarboxylic acid. In some embodiments, the carboxylic acid is selectedfrom the group consisting of acetic acid, glycolic acid, lactic acid,lipoic acid, pivalic acid, isobutryic acid, butyric acid, propionicacid, formic acid, and carbonic acid. In some embodiments, the activekeratolytic agent is a thiol.

In some embodiments, a compound or a pharmaceutical compositioncomprising any compound provided herein, such as a compound of any oneof Formula (Ia), Formula (Ib), Formula (Ic), Formula (I), Formula (I′),or Formula (II), or a pharmaceutically acceptable salt thereof. Incertain embodiments, the composition further comprises an amount of afree form of a radical of any of Formula (Ia), Formula (Ib), Formula(Ic), Formula (I), Formula (I′), or Formula (II) or the like (such aswherein the free form is the radical, wherein R is a negative charge oran H). In some embodiments, a composition provided herein comprises a(e.g., weight or molar) ratio of a compound provided herein to a freeform of a radical of Formula (Ia), Formula (Ib), Formula (Ic), Formula(I), Formula (I′), or Formula (II), or a pharmaceutically acceptablesalt thereof (e.g., wherein R is a negative charge or an H) is about1:99 to about 100:0 (e.g., the amount of the free form of the radicalrelative to the overall amount of free form of the radical plus theconjugate is between 0% (weight or molar) and 99%). In some embodiments,the relative amount of the free form of the radical is 0% to about 50%,such 0% to about 20%, 0% to about 10%, about 0.1% to about 10%, about0.1% to about 5%, less than 5%, less than 2.5%, less than 2%, or thelike (percentages being weight/weight or mole/mole percentages). In someinstances, such aqueous compositions are pre-manufactured or aremanufactured at the time of application in order to maintain highconcentrations of the compound relative to the free form of a radicalthereof. In some embodiments, such concentrations of the compound arepresent in the composition for at least 45 minutes in an aqueouscomposition (such as in an aqueous composition, e.g., a HEPES buffer,such as under the conditions described herein, such as in Tables 2 and3). Tables 2 and 3 of the Examples illustrate good stability of thecompositions provided herein and such recitations are incorporated inthe disclosure hereof. Further, in some instances, compounds providedherein release free form of a radical of a compound of Formula (Ia),Formula (Ib), Formula (Ic), Formula (I), Formula (I′), or Formula (II)(e.g., wherein R is a negative charge or H), such as when administeredto an individual (e.g., ocular (e.g., peri-ocular) or dermatologicaladministration). In more specific instances, when administered to anindividual at a location with esterases present, rapid release of active(free) forms of a radical of Formula (Ia), Formula (Ib), Formula (Ic),Formula (I), Formula (I′), or Formula (II) (e.g., wherein R is anegative charge or H) (and, a keratolytic agent and/or agent thatfurther produces active keratolytic agent(s) (e.g., by furtherhydrolysis thereof)).

One embodiment provides a method of treating an ophthalmic disease ordisorder in a patient in need of thereof, comprising administering tothe patient a composition comprising any compound provided herein, suchas a compound of any one of Formula (Ia), Formula (Ib), Formula (Ic),Formula (I), Formula (I′), or Formula (II), or a pharmaceuticallyacceptable salt thereof. Another embodiment provides the method whereinthe ophthalmic disease or disorder is selected from dry eye, lid wiperepitheliopathy (LWE), contact lens discomfort (CLD), contact lensdiscomfort, dry eye syndrome, evaporative dry eye syndrome, aqueousdeficiency dry eye syndrome, blepharitis, keratitis, meibomian glanddysfunction, conjunctivitis, lacrimal gland disorder, inflammation ofthe anterior surface of the eye, infection of the anterior surface ofthe eye, infection of the lid, demodex lid infestation, lid wiperepitheliopathy and autoimmune disorder of the anterior surface of theeye.

In certain embodiments, provided herein is a method of treating anocular (e.g., peri-ocular) or dermatological indication (e.g.,associated with keratolytic activity, inflammation, and/or microbialinfiltration), the method comprising administering a therapeuticallyeffective amount of a compound or composition provided herein. In someembodiments, a composition provided herein (e.g., used in a methodprovided herein) comprises a compound provided herein in atherapeutically effective amount (e.g., at a concentration effective totreat keratosis/keratolytic activity, inflammation, and/or microbialinfiltration), in the eye, surrounding tissue, or skin. In certainembodiments, a (e.g., pharmaceutical and/or ophthalmic) compositionprovided herein comprises about 0.1 wt. % to about 10 wt. % of acompound provided herein.

Ocular and/or dermatological disorders include inflammatory conditionsof the eyelids (e.g., hordeolum (stye), blepharitis, and chalazion),ocular surface (e.g., dry eye disease and anterior uveitis) andposterior eye (e.g., posterior and pan-uveitis), abnormalities of theperi-ocular glands (e.g., meibomian gland dysfunction (MGD)),allergic-type conditions, (e.g., eczema, atopic dermatitis, atopickeratoconjunctivitis refractory to topical steroid treatment, and vernalkeratoconjunctivitis), surgical complications (e.g., corneal transplantrejection, post-corneal transplant glaucoma, cataracts secondary tophakic corneal transplant, fungal infections in keratoplasty patients,and post-LASIK dry eye and/or poor refractive outcomes), cornealabnormalities (e.g., inflammatory corneal ulceration, rheumatoid cornealulcers, and Thygeson's superficial punctate keratitis), conjunctivalabnormalities (e.g., iridocyclitis, ligneous conjunctivitis), ocularcomplications from systemic treatments and/or autoimmune diseases (e.g.,pauciarticular juvenile rheumatoid arthritis, graft versus host disease,and sjogren's syndrome) and/or infectious disease of the anteriorsurface of the eye. Provided herein are compositions and methods for thetreatment of ocular and periocular abnormalities that are known to havemultifactorial etiologies and interactions.

One embodiment provides a compound having the structure of Formula(III):

X is a bond or —O—;

R⁸ is hydrogen, alkyl, heteroalkyl, or haloalkyl;

R⁹ is alkyl or heteroalkyl, the alkyl or heteroalkyl being optionallysubstituted,

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, R⁸ is hydrogen, alkyl, or haloalkyl. In someembodiments, R⁸ is C₁-C₄ alkyl. In some embodiments, R⁸ is methyl.

In some embodiments, X is a bond. In some embodiments, R⁹ is alkyloptionally substituted with one or more substituent(s), each substituentbeing independently selected from the group consisting of —OH andoptionally substituted alkyl. In some embodiments, the alkyl issubstituted with alkyl or heterocycloalkyl. In some embodiments, theheterocycloalkyl is further optionally substituted. In some embodiments,R⁹ is alkyl substituted with —OH. In some embodiments, R⁹ is alkylsubstituted with —OH and alkyl. In some embodiments, R⁹ is alkylsubstituted with a dithiolane. In some embodiments, R⁹ is C₁-C₄ alkyl.

In some embodiments, R⁹ is C₁-C₄ alkyl, —CH(CH₃)OH, —CH₂OH, or

In some embodiments, X is —O—. In some embodiments, R⁸ is methyl and R⁹is alkyl further optionally substituted with one or more substituent(s),each substituent being independently selected from the group consistingof alkyl, heteroalkyl (e.g., hydroxymethyl or ester), andheterocycloalkyl, wherein the heteroalkyl (e.g., hydroxymethyl or ester)or heterocycloalkyl is further optionally substituted. In someembodiments, R⁹ is alkyl further substituted with an optionallysubstituted 1,3-dioxane. In some embodiments, R⁹ is alkyl furthersubstituted with 1,3-dioxane. In some embodiments, R⁹ is alkyl furthersubstituted with 2,2-dimethyl-1,3-dioxane or 2-methyl-1,3-dioxane. Insome embodiments, R⁹ is alkyl further substituted with one or moreheteroalkyl substituents. In some embodiments, the heteroalkylsubstituent is —CH₂OH or —O(C═O)C₁-C₄ alkyl. In some embodiments, R⁹ isalkyl further substituted with alkyl, wherein the alkyl is furthersubstituted with an ester further substituted with alkyl, wherein thealkyl is further optionally substituted with one or more substituent(s),each substituent being independently selected from the group consistingof —OH and alkyl. In some embodiments, R⁹ is C₁-C₄ alkyl. In someembodiments, R⁹ is alkyl further substituted with methyl and—O(C═O)C₁-C₄ alkyl.

In some embodiments, R⁹ is C₁-C₄ alkyl,

In some embodiments, C₁-C₄ alkyl is methyl, ethyl, propyl, isopropyl, ortert-butyl.

In certain embodiments, described herein is a method of treating a(e.g., ophthalmic or dermal) disease or disorder (e.g., any disease ordisorder described herein) in an individual in need of thereof,comprising administering (e.g., topically to the eye and/or skin) to theindividual a composition (e.g., any composition described herein)comprising any compound provided herein, such as a compound of any oneof Formula (III), or a pharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference for the specificpurposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION Certain Definitions

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary between 1% and 15% of the stated number or numericalrange. The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, may “consist of” or “consist essentially of” thedescribed features.

The terms “treat,” “treating,” or “treatment” as used herein, includereducing, alleviating, abating, ameliorating, relieving, or lesseningthe symptoms associated with a disease, disease sate, or indication(e.g., MGD) in either a chronic or acute therapeutic scenario. In oneembodiment, treatment includes a reduction of a terminal ductobstruction. Also, treatment of a disease or disease state describedherein includes the disclosure of use of such compound or compositionfor the treatment of such disease, disease state, or indication.

The term “opening” refers to the clearing (at least in part) of anobstructed meibomian gland canal or orifice and/or maintaining thepatency of the meibomian gland canal or orifice.

The term “keratolytic agent” and/or “keratoplastic agent” as used hereinrefers to an agent that softens, disrupts, dissolves, solubilizes, orloosens a keratinized obstruction, or prevents the formation of akeratinized obstruction. Specifically, the term “keratolytic agents”refers to agents used to promote softening and dissolution of keratinand the term “keratoplastic agents” refers to agents used to reducekeratin production.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” generally refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, such as havingfrom one to fifteen carbon atoms (e.g., C₁-C₁₅ alkyl). Unless otherwisestate, alkyl is saturated or unsaturated (e.g., an alkenyl, whichcomprises at least one carbon-carbon double bond). Disclosures providedherein of an “alkyl” are intended to include independent recitations ofa saturated “alkyl,” unless otherwise stated. Alkyl groups describedherein are generally monovalent, but may also be divalent (which mayalso be described herein as “alkylene” or “alkylenyl” groups). Incertain embodiments, an alkyl comprises one to thirteen carbon atoms(e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkyl comprises one toeight carbon atoms (e.g., C₁-C₈ alkyl). In other embodiments, an alkylcomprises one to five carbon atoms (e.g., C₁-C₅ alkyl). In otherembodiments, an alkyl comprises one to four carbon atoms (e.g., C₁-C₄alkyl). In other embodiments, an alkyl comprises one to three carbonatoms (e.g., C₁-C₃ alkyl). In other embodiments, an alkyl comprises oneto two carbon atoms (e.g., C₁-C₂ alkyl). In other embodiments, an alkylcomprises one carbon atom (e.g., C₁ alkyl). In other embodiments, analkyl comprises five to fifteen carbon atoms (e.g., C₅-C₁₅ alkyl). Inother embodiments, an alkyl comprises five to eight carbon atoms (e.g.,C₅-C₈ alkyl). In other embodiments, an alkyl comprises two to fivecarbon atoms (e.g., C₂-C₅ alkyl). In other embodiments, an alkylcomprises three to five carbon atoms (e.g., C₃-C₅ alkyl). In otherembodiments, the alkyl group is selected from methyl, ethyl, 1-propyl(n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl),1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. In general, alkylgroups are each independently substituted or unsubstituted. Eachrecitation of “alkyl” provided herein, unless otherwise stated, includesa specific and explicit recitation of an unsaturated “alkyl” group.Similarly, unless stated otherwise specifically in the specification, analkyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a)), —C(O)R^(a),—C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is optionally substituted as described for“alkyl” groups.

“Alkylene” or “alkylene chain” generally refers to a straight orbranched divalent alkyl group linking the rest of the molecule to aradical group, such as having from one to twelve carbon atoms, forexample, methylene, ethylene, propylene, i-propylene, n-butylene, andthe like. Unless stated otherwise specifically in the specification, analkylene chain is optionally substituted as described for alkyl groupsherein.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)7-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)R^(a)(where t is 1 or 2), —R^(b)—S(O)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” or “aryl-alkyl” refers to a radical of the formula —R^(c)-arylwhere R^(c) is an alkylene chain as defined above, for example,methylene, ethylene, and the like. The alkylene chain part of thearalkyl radical is optionally substituted as described above for analkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” or “cycloalkyl” refers to a stable non-aromatic monocyclicor polycyclic hydrocarbon radical consisting solely of carbon andhydrogen atoms, which includes fused or bridged ring systems, havingfrom three to fifteen carbon atoms. In certain embodiments, acarbocyclyl comprises three to ten carbon atoms. In other embodiments, acarbocyclyl comprises five to seven carbon atoms. The carbocyclyl isattached to the rest of the molecule by a single bond. Carbocyclyl orcycloalkyl is saturated (i.e., containing single C—C bonds only) orunsaturated (i.e., containing one or more double bonds or triple bonds).Examples of saturated cycloalkyls include, e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Anunsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examplesof monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicalsinclude, for example, adamantyl, norbornyl (i.e.,bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwisestated specifically in the specification, the term “carbocyclyl” ismeant to include carbocyclyl radicals that are optionally substituted byone or more substituents independently selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)R^(a)(where t is 1 or 2), —R^(b)—S(O)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkenyl” refers to a radical of the formula—R^(c)-carbocyclyl where R^(c) is an alkenylene chain as defined above.The alkenylene chain and the carbocyclyl radical is optionallysubstituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula—R^(c)-carbocyclyl where R^(c) is an alkynylene chain as defined above.The alkynylene chain and the carbocyclyl radical is optionallysubstituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R is an alkylene chain as definedabove. The alkylene chain and the carbocyclyl radical is optionallysubstituted as defined above.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Insome embodiments, the alkyl part of the fluoroalkyl radical isoptionally substituted as defined above for an alkyl group.

The term “heteroalkyl” refers to an alkyl group as defined above inwhich one or more skeletal carbon atoms of the alkyl are substitutedwith a heteroatom (with the appropriate number of substituents orvalencies—for example, —CH₂— may be replaced with —NH— or —O—). Forexample, each substituted carbon atom is independently substituted witha heteroatom, such as wherein the carbon is substituted with a nitrogen,oxygen, selenium, or other suitable heteroatom. In some instances, eachsubstituted carbon atom is independently substituted for an oxygen,nitrogen (e.g. —NH—, —N(alkyl)-, or —N(aryl)- or having anothersubstituent contemplated herein), or sulfur (e.g. —S—, —S(═O)—, or—S(═O)₂—). In some embodiments, a heteroalkyl is attached to the rest ofthe molecule at a carbon atom of the heteroalkyl. In some embodiments, aheteroalkyl is attached to the rest of the molecule at a heteroatom ofthe heteroalkyl. In some embodiments, a heteroalkyl is a C₁-C₁₈heteroalkyl. In some embodiments, a heteroalkyl is a C₁-C₁₂ heteroalkyl.In some embodiments, a heteroalkyl is a C₁-C₆ heteroalkyl. In someembodiments, a heteroalkyl is a C₁-C₄ heteroalkyl. Representativeheteroalkyl groups include, but are not limited to —OCH₂OMe, or—CH₂CH₂OMe. In some embodiments, heteroalkyl includes alkoxy,alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl,heterocycloalkyl, and heterocycloalkylalkyl, as defined herein. Unlessstated otherwise specifically in the specification, a heteroalkyl groupis optionally substituted as defined above for an alkyl group.

“Heteroalkylene” refers to a divalent heteroalkyl group defined abovewhich links one part of the molecule to another part of the molecule.Unless stated specifically otherwise, a heteroalkylene is optionallysubstituted, as defined above for an alkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, whichoptionally includes fused or bridged ring systems. The heteroatoms inthe heterocyclyl radical are optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl is attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)R^(a)(where t is 1 or 2), —R^(b)—S(O)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) 7-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)R^(a)(where t is 1 or 2), —R^(b)—S(O)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein, in some embodiments, contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

In general, optionally substituted groups are each independentlysubstituted or unsubstituted. Each recitation of an optionallysubstituted group provided herein, unless otherwise stated, includes anindependent and explicit recitation of both an unsubstituted group and asubstituted group (e.g., substituted in certain embodiments, andunsubstituted in certain other embodiments). Unless otherwise stated,substituted groups may be substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a)), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

The compounds disclosed herein, reference to any atom includes referenceto isotopes thereof. For example reference to H includes reference toany isotope thereof, such as a ¹H, ²H, ³H, or mixtures thereof.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the dual-actingmeibomian gland dysfunction pharmacological agents described herein isintended to encompass any and all pharmaceutically suitable salt forms.Preferred pharmaceutically acceptable salts of the compounds describedherein are pharmaceutically acceptable acid addition salts andpharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are, in some embodiments, prepared by contacting the free baseforms with a sufficient amount of the desired acid to produce the saltaccording to methods and techniques with which a skilled artisan isfamiliar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts are, insome embodiments, formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supra.

Meibomian Gland

The meibomian glands are large sebaceous glands located in the eyelids,and unlike skin, are unassociated with hair. The meibomian glandsproduce the lipid layer of the tear film that protects it againstevaporation of the aqueous phase. The meibomian gland orifice is locatedon the epithelial side of the lid margin, and is only a few hundredmicrons from the mucosal side. The glands are located on both upper andlower eyelids, with higher amounts of the glands on the upper eyelid. Asingle meibomian gland is composed of clusters of secretory acini thatare arranged circularly around a long central duct and connected to itby short ductules. The terminal part of the central duct is lined by aningrowth of the epidermis that covers the free lid margin and forms ashort excretory duct that opens as an orifice at the posterior part ofthe lid margin just anterior to the mucocutaneous junction near theinner lid border. The oily secretion composed of lipids is synthesizedwithin the secretory acini. The lipid secretion is a liquid at near bodytemperature and is delivered to the skin of the lid margin as a clearfluid, called “meibum.” It forms shallow reservoirs on the upper andlower lid margins, and consists of a complex mixture of cholesterol,wax, cholesteryl esters, phospholipids, with small amounts oftriglycerides, triacylglycerols, and hydrocarbons. The separatemeibomian glands are arranged in parallel, and in a single rowthroughout the length of the tarsal plates in the upper and lower lids.The extent of the glands corresponds roughly to the dimensions of thetarsal plates.

The term “keratinized obstruction” as used herein refers to a blockageof the meibomian gland, regardless of the location of the blockage. Insome embodiments, the blockage is complete, whereas in otherembodiments, the blockage is partial. Regardless of the degree ofblockage, such keratinized obstruction leads to meibomian glanddysfunction. In some embodiments, the keratinized obstruction iscomposed of keratinized material and lipids. In some embodiments, thekeratinized obstruction is a blockage at the meibomian gland orifice andexcretory duct. In some embodiments, the keratinized obstruction iscaused by keratinization of the epithelium at the lid margin andmeibomian gland. In certain instances, the keratin obstruction isinfluenced by the migration or aberrant differentiation of stem cells.In some embodiments, the keratinized obstruction results in reduceddelivery of oil to the lid margin and tear film, and stasis inside themeibomian gland that causes increased pressure, resultant dilation,acinar atrophy, and low secretion. In certain instances, keratinizationof the meibomian gland causes degenerative gland dilation and atrophy.

Ocular Surface Diseases or Disorders

Ocular surface diseases is a group of diseases including, but notlimited to, dry eye syndrome (including evaporative DES and/or aqueousdeficiency DES), blepharitis, keratitis, meibomian gland dysfunction,conjunctivitis, lacrimal gland disorder, contact lens related conditionsand inflammatory, infectious, or autoimmune diseases or disorders of theanterior surface of the eye. The term, “meibomian gland dysfunction,” asused herein, refers to chronic, diffuse abnormality of the meibomianglands, that is characterized by terminal duct obstruction orqualitative or quantitative changes in the glandular secretion, or both.MGD may result in alteration of the tear film, eye irritation symptoms,inflammation, or ocular surface disease. The most prominent aspects ofMGD are obstruction of the meibomian gland orifices and terminal ductsand changes in the meibomian gland secretions.

In some instances, meibomian gland dysfunction (MGD) is a chronic,diffuse abnormality of the meibomian glands, commonly characterized byterminal duct obstruction and/or qualitative/quantitative changes in theglandular secretion. Terminal duct obstruction is caused byhyperkeratinization of the ductal epithelium (Nichols et al, Inv. Oph. &Vis. Sci. (2011); 52(4):1922-1929). These alterations in both meibumquality and expression may result in alteration of the tear film,symptoms of eye irritation, and ocular surface disease such asevaporative dry eye. The principal clinical consequence of MGD isevaporative dry eye syndrome and large population based studies (i.e.,Bankok Study and the Shihpai Eye Study) estimate that over 60% ofpatients with dry eye symptoms also have MGD (Schaumberg et al,Investigative Ophthalmology and Visual Science. (2011);52(4):1994-2005).

MGD is a leading contributor of dry eye syndrome. The occurrence of dryeye syndrome is widespread and affects about 20 million patients in theUnited States alone. Dry eye syndrome is a disorder of the ocularsurface resulting from either inadequate tear production or excessiveevaporation of moisture from the surface of the eye. Tears are importantto corneal health because the cornea does not contain blood vessels, andrelies on tears to supply oxygen and nutrients. Tears and the tear filmare composed of lipids, water, and mucus, and disruption of any of thesecan cause dry eye. An inadequate amount of lipids flowing from themeibomian glands as caused by a keratinized obstruction, may causeexcessive evaporation, thereby causing dry eye syndrome.

In some embodiments, altered meibomian gland secretion is detected byphysically expressing the meibomian glands by applying digital pressureto the tarsal plates. In subjects without MGD, the meibum is a pool ofclear oil. In MGD, both the quality and expressibility of the expressedmaterial is altered. The altered meibum is also known as meibomianexcreta and is made up of a mixture of altered secretions andkeratinized epithelial material. In MGD, the quality of expressed lipidvaries in appearance from a clear fluid, to a viscous fluid containingparticulate matter and densely opaque, toothpaste-like material. Themeibomian orifices may exhibit elevations above surface level of thelid, which is referred to as plugging or pouting, and is due toobstruction of the terminal ducts and extrusion of a mixture ofmeibomian lipid and keratinized material.

Obstructive MGD is characterized by all or some of the following: 1)chronic ocular discomfort, 2) anatomic abnormalities around themeibomian gland orifice (which is one or more of the following: vascularengorgement, anterior or posterior displacement of the mucocutaneousjunction, irregularity of the lid margin) and 3) obstruction of themeibomian glands (obstructive findings of the gland orifices by slitlamp biomicroscopy (pouting, plugging or ridge), decreased meibumexpression by moderate digital pressure).

Current methods for assessing and monitoring MGD symptoms include, butare not limited to patient questionnaires, meibomian gland expression,tear stability break up time, and determining the number of patentglands as seen by digital expression.

In some embodiments, the symptoms of a patient are assessed by askingthe patient a series of questions. Questionnaires allow the assessmentof a range of symptoms associated with ocular discomfort. In someembodiments, the questionnaire is the SPEED questionnaire. The SPEEDquestionnaire assesses frequency and severity of a patient's dry eyesymptoms. It examines the occurrence of symptoms on the current day,past 72 hours and past three months. A SPEED score is tallied based onthe patient's answers to the questions, to give a range of severity ofthe patient's symptoms. The SPEED questionnaire includes questions suchas the following: 1) what dry eye symptoms are you experiencing, andwhen do they occur? 2) how frequently do you experience dryness,grittiness, or scratchiness in your eyes? 3) how often do you experiencesoreness or irritation of the eyes? 4) how often do you experienceburning or watering of the eyes?5) how often do you experience eyefatigue? and 6) how severe are the symptoms?

Meibomian gland expressibility is optionally determined to assess themeibomian gland function. In normal patients, meibum is a clear to lightyellow oil. Meibum is excreted from the glands when digital pressure isplaced on the glands. Changes in meibomian gland expressibility are onepotential indicator of MGD. In some embodiments, during expression,quantifying the amount of physical force applied during expression ismonitored in addition to assessing lipid volume and lipid quantity.

Tear stability break up time (TBUT) is a surrogate marker for tearstability. Tear film instability is a core mechanism in dry eye and MGD.Low TBUT implies a possibility of lipid layer compromise and MGD. TBUTis optionally measured by examining fluorescein breakup time, as definedas the time to initial breakup of the tear film after a blink.Fluorescein is optionally applied by wetting a commercially availablefluorescein-impregnated strip with saline, and applied to the inferiorfornix or bulbar conjuctiva. The patient is then asked to blink severaltimes and move the eyes. The break up is then analyzed with a slit lamp,a cobalt blue filter, and a beam width of 4 mm. The patient isinstructed to blink, and the time from upstroke of the last blink to thefirst tear film break or dry spot formation is recorded as ameasurement.

Other methods for assessing MGD symptoms, include but are not limitedto, Schirmer test, ocular surface staining, lid morphology analysis,meibography, meibometry, interferometry, evaporimetry, tear lipidcomposition analysis, fluorophotometry, meiscometry, osmolarityanalysis, indices of tear film dynamics, evaporation and tear turnover.

Current treatments for MGD include lid warming, lid massage, lidhygiene, lid expression and meibomian gland probing. Pharmacologicalmethods, prior to those described herein, have not been used.

Lid hygiene is considered the primary treatment for MGD and consists ofthree components: 1) application of heat, 2) mechanical massage ofeyelids and 3) cleansing the eyelid. Eyelid warming procedures improvemeibomian gland secretion by melting the pathologically alteredmeibomian lipids. Warming is achieved by warm compresses or devices.Mechanical lid hygiene includes the use of scrubs, mechanical expressionand cleansing with various solutions of the eyelashes and lid margins.Lid margins are optionally also cleansed with hypoallergenic bar soap,dilute infant shampoo or commercial lid scrubs. Physical expression ofmeibomian glands is performed in a physician's office or is performed bythe patient at home. The technique varies from gentle massage of thelids against the eyeball to forceful squeezing of the lids eitheragainst each other or between a rigid object on the inner lid surfaceand a finger, thumb, or rigid object (such as a glass rod, cotton swab,or metal paddle) on the outer lid surface. The rigid object on the innerlid surface protects the eyeball from forces transferred through theeyelid during expression and to offer a stable resistance, to increasethe amount of force that is applied to the glands.

Eyelid warming is limited because the warming melts the lipids, but doesnot address movement of the keratinized material. Further, eyelidwarming induces transient visual degradation due to corneal distortion.Mechanical lid hygiene is also limited because the force needed toremove an obstruction can be significant, resulting in significant painto the patient. The effectiveness of mechanical lid hygiene is limitedby the patient's ability to tolerate the associated pain during theprocedure. Other treatments for MGD are limited.

Physical opening of meibomian glands obstruction by meibomian glandexpression is an acceptable method to improve meibomian gland secretionand dry eye symptoms. In addition probing of the meibomian gland canalhas been used to open the obstructed canal. Both methods, expression andprobing, are limited, however, by the pain induced by the procedure, thepossible physical insult to the gland and canal structures and theirshort lived effect estimated at days and weeks. Therefore, methods areneeded to improve patient comfort, which will not cause harm to themeibomian glands and canals, that will reduce the dependency on frequentoffice visits and improve secretion of meibum.

U.S. Pat. No. 9,463,201 entitled, “Compositions and methods for thetreatment of meibomian gland dysfunction” describes a method fortreating meibomian gland dysfunction involving the topicaladministration of a therapeutically-effective amount of at least onekeratolytic agent in an ophthalmically-acceptable carrier. The patentincludes keratolytic agents that are inorganic selenium (Se) compoundssuch as selenium disulfide (SeS₂) or organoselenium compounds such asEbselen (2-Phenyl-1,2-benzoselenazol-3-one). This agent would treat theunderlying cause of MGD, but not a “plus” inflammatory disease asdescribed by the DEWS report on MGD.

The role of inflammation in the etiology of MGD is controversial. Theterms posterior blepharitis and MGD are not synonymous. Posteriorblepharitis describes inflammatory conditions of the posterior lidmargin and has various causes, of which MGD is only one possible cause(Nichols et al 2011). In its earliest stages, MGD is not associated withclinical signs characteristic of posterior blepharitis. As MGDprogresses, an MGD-related posterior blepharitis is said to be present.MGD-related posterior blepharitis affects the meibomian glands andmeibomian gland orifices. MGD-related posterior blepharitis ischaracterized by flora changes, esterase and lipase release, lipidchanges, and eyelid inflammation. Hyperkeratinization of the meibomiangland epithelium (thickening of the lining of the glands) may lead toobstruction and a decrease in the quantity of meibomian gland secretionsand may be responsible for MGD-related posterior blepharitis. Diagnosisof MGD-related posterior blepharitis includes meibomian gland expressionwith demonstration of an altered quality of expressed secretions, and/orby a loss of gland functionality (decreased or absent expressibility).The TFOS report on Meibomian Gland Disease specifically notes thatanterior blepharitis and exacerbated inflammatory ocular surface diseaseare “plus” diseases to MGD which are managed by topical, ocular steroids(Nichols et al 2011). Since these “plus” conditions can be present invarious levels of severity from early to late MGD there is a need fortreatments and/or combinations of treatments that can target both theunderlying non-inflammatory pathophysiology of MGD and inflammationassociated with these comorbid conditions.

MGD-related inflammatory eye disease may comprise a different mechanismthan blepharitis-related MGD. MGD-related inflammatory eye disease ischaracterized by an inflammatory cascade involving activation andmigration of T lymphocytes to the inflamed tissue. T lymphocyteinfiltration may result in lacrimal gland stimulation and upregulationof cytokines. Exemplary cytokines that may be involved in MGD-relatedinflammatory eye disease include, but are not limited to, interleukin-1,interleukin-4, interleukin-6, inteleukin-8, interferon gamma, macrophageinflammatory protein 1 alpha, and tumor necrosis factor alpha. Kinasepathways including the mitogen activated protein kinase (MAPK) pathwayare also activated in the inflammatory cascade. The inflammatory processresults in loss of mucin-producing goblet cells and destruction of theocular surface that can lead to further damage.

Dry eye syndrome, also known as keratoconjunctivitis sicca (KCS), isconsidered a self-sustaining disease that is progressively disconnectedfrom its initial cause. Dry eye syndrome is associated with inflammationat the ocular surface and periocular tissue. Inflammation ischaracterized by the activation and migration of T lymphocytes to theinflamed tissue including in the conjunctiva and lacrimal glands.Inflammatory cytokines, chemokines, and matrix metalloproteinase havealso been identified as being increased.

Animal models of dry eye disease have been established and reviewed(Barabino, et al, (Invest. Ophthalmol. Vis. Sci. 2004, 45:1641-1646)).Barabino, et al, (Invest. Ophthalmol. Vis. Sci. 2005, 46:2766-2771)described a model wherein exposure of normal mice to a low-humidityenvironment in a controlled-environment chamber leads to significantalterations in tear secretion, goblet cell density, and acquisition ofdry eye-related ocular surface signs. However, no single animal modeladequately accounts for the immune, endocrine, neuronal andenvironmental factors which contribute to dry eye pathogenesis.

Anti-inflammatory agents may be used to treat ocular surface diseases ordisorders including dry eye syndrome. Corticosteroids are an effectiveanti-inflammatory therapy in dry eye disease. For example, in a 4-week,double-masked, randomized study in 64 patients with dry eye and delayedtear clearance, loteprednol etabonate 0.5% ophthalmic suspension(Lotemax [Bausch and Lomb, Rochester, N.Y.]), QID, was found to be moreeffective than its vehicle in improving some signs and symptoms(Pflugfelder et al, Am J Ophthalmol (2004); 138:444-57). The TFOS 2007report on dry eye disease went so far as to conclude that, “In the USFederal Regulations, ocular corticosteroids receiving “class labelling”are indicated for the treatment “ . . . of steroid responsiveinflammatory conditions of the palpebral and bulbar conjunctiva, corneaand anterior segment of the globe such as allergic conjunctivitis, acnerosacea, superficial punctate keratitis, herpes zoster keratitis,iritis, cyclitis, selected infective conjunctivitis, when the inherenthazard of steroid use is accepted to obtain an advisable diminution inedema and inflammation.” KCS, in some instances, is included in thislist of steroid-responsive inflammatory conditions (Therapy Subcommitteeof the International Dry Eye WorkShop, 2007. Management and Therapy ofDry Eye Disease: Report of the Management and Therapy Subcommittee ofthe International Dry Eye WorkShop (2007). 2007; 5: 163-178).” While theUS FDA does not agree with this conclusion, short courses of steroids,especially Lotemax, are commonly used to treat inflammation associatedwith dry eye disease.

Other anti-inflammatory agents include nonsteroidal anti-inflammatorydrugs (NSAIDs). NSAIDs inhibit the activity of cyclooxygenases includingcyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are enzymesinvolved in the synthesis of prostaglandins and thromboxanes fromarachidonic acid. Prostaglandin and thromboxane signaling are involvedin inflammation and immune modulation. In some cases, NSAIDs are usedfor treating dry eye disease by treating the inflammation at the ocularsurface.

Treatment of dry eye is also accomplished through agents that enhancetear fluid and mucin production. For example, agonists of the P2Y₂receptor have been shown to increase tear fluid and mucin secretion. Themechanism is thought to involve P2Y₂ signalling to raise intracellularcalcium and open chloride channels in the apical membrane. The P2Y₂receptor belongs to the family of purinergic receptors, which have beenclassified into P1 receptors and P2 receptors on the basis of theirnative agonism by purine nucleosides and purine and pyrimidinenucleotides, respectively. P2 receptors are further distinguishedphysiologically into two types: P2X receptors and P2Y receptors. The P2Yreceptors are involved in diver signaling including plateletaggregation, immunity, lipid metabolism, and bone activity. Severalstudies have also demonstrated the presence of P2X and P2Y receptors inocular tissues, including the retina, ciliary body, and lens. Thesestudies indicate that P2Y₂ receptors appear to be the main subtype ofpurinergic receptor located at the ocular surface. P2Y₂ receptors havealso been demonstrated to be localized in ocular tissues in theconjunctival epithelial goblet and serous cells and meibomian glandacinus and ductal epithelial cells of the rhesus macaque.

Lifitegrast

The chemical name for lifitegrast is(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoicacid having a molecular formula of C₂₉H₂₄Cl₂N₂O₇S and a molecular weightis 615.5. Lifitegrast is typically administered as a 5% ophthalmicsolution with a pH of 7.0-8.0 and an osmolality range of 200-330mOsmol/kg. The structural formula of lifitegrast is:

(S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoicacid

Lifitegrast is indicated for the treatment of the signs and symptoms ofdry eye disease (DED). Lifitegrast binds to the integrin lymphocytefunction-associated antigen-1 (LFA-1), a cell surface protein found onleukocytes and blocks the interaction of LFA-1 with its cognate ligandintercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressedin corneal and conjunctival tissues in dry eye disease. LFA-1/ICAM-1interaction can contribute to the formation of an immunological synapseresulting in T-cell activation and migration to target tissues. In vitrostudies demonstrated that lifitegrast may inhibit T-cell adhesion toICAM-1 in a human T-cell line and may inhibit secretion of inflammatorycytokines in human peripheral blood mononuclear cells. The exactmechanism of action of lifitegrast in dry eye disease is not known. Moreinformation about lifitegrast can be found in the following U.S. Pat.Nos. 10,124,000, 7,314,938, 7,745,460, 7,790,743, 7,928,122, 8,084,047,8,168,655, 8,367,701, 8,592,450, 8,927,574, 9,085,553, 9,216,174,9,353,088, 9,447,077, and 9,890,141.

GW-559090

The chemical name for GW-559090 is(S)-3-(4-((4-carbamoylpiperidine-1-carbonyl)oxy)phenyl)-2-((S)-4-methyl-2-(2-(o-tolyloxy)acetamido)pentanamido)propanoicacid having a molecular formula of C₃₁H₄₀N₄O₈ and a molecular weight of596.7. The structural formula of GW-559090 is:

(S)-3-(4-((4-carbarmoylpiperidine-1-carbonyl)oxy)phenyl)-2-((S)-4-methyl-2-(2-(o-tolyloxy)acetamido)pentanamido)propanoicAcid

GW-559090 is a potent integrin a4 antagonist (Ravensberg et al, Allergy(2006) 61, 1097-1103) that has demonstrated improvements in objectivesigns of dry eye in the murine DS model. The potent integrin a4antagonist was found to act locally at the level of the ocular surface,presumably by preventing the migration of antigen-presenting cells tothe draining lymph nodes with a resulting interruption of the immunecycle of dry eye (Invest. Ophthalmol. Vis. Sci. (2015) 56(10),5888-5895).

Meibomian Gland Dysfunction and Dry Eye Disease Pharmacological AgentsKeratolytic Conjugates as Dual-acting Agents

Described herein are dual-acting agents which address simultaneously thenon-inflammatory keratolytic blockage component of meibomian glanddysfunction and the inflammation associated dry eye disease includingaqueous deficiency. The keratolytic conjugates described herein areuseful as either an acute therapy (e.g., by a trained specialist orphysician) or as a chronic therapy (e.g., in the hands of a patient, oralternatively, by a trained specialist or physician). The keratolyticconjugates are tested, in certain embodiments, using the assays andmethods described herein (e.g., as described in the examples). Thekeratolytic conjugates described herein represent a significant advancein the art as the first-order metabolites obtained from metabolism ofthe agents are operative against both the keratolytic and theinflammatory component of dry eye disease.

One embodiment provides a compound, having the structure of Formula(Ia):

wherein

R¹ is aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein the aryl,cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted;

R², R³, and R⁴ are each independently H, cyano, halo, ester, alkoxy,alkyl, heteroalkyl, cycloalkyl or heterocyclyl, wherein the alkoxy,alkyl, heteroalkyl, cycloalkyl or heterocyclyl is optionallysubstituted;

R⁵ is -L-R^(5a), wherein L is a bond, alkyl, or heteroalkyl, and R^(a)is absent, a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl,wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl isoptionally substituted;

R⁶ is H, alkyl, or heteroalkyl;

each R⁷ is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl,cycloalkyl or haloalkyl;

n is 0-6;

R is -L′-D, wherein:

D is a keratolytic agent; and

L′ is a linker,

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, L′ comprises one or more linker groups, whereineach linker group is selected from the group consisting of a bond, —O—,—S—, alkyl (alkylenyl), heteroalkyl (heteroalkylenyl), disulfide, esterand carbonyl. In some embodiments, the keratolytic agent comprises oneor more group (e.g., keratolytic group), each group (e.g., keratolyticgroup) being independently selected from the group consisting of thiol,disulfide, selenium (e.g., selenide, diselenide), and carboxylic acid.

In certain aspect, the disclosure provides a compound having thestructure of Formula (Id):

wherein

R¹ is aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein the aryl,cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted;

R², R³, and R⁴ are each independently H, cyano, halo, ester, alkoxy,alkyl, heteroalkyl, cycloalkyl or, heterocyclyl, wherein the alkoxy,alkyl, heteroalkyl, cycloalkyl or, heterocyclyl is optionallysubstituted;

R⁵ is -L-R^(a), wherein L is a bond, alkyl, or heteroalkyl, and R^(a) isabsent, a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl,wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl isoptionally substituted;

R⁶ is H, alkyl, or heteroalkyl;

each R⁷ is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl,cycloalkyl, or haloalkyl;

n is 0-6;

Y is O or S; and

R is alkyl or heteroalkyl substituted with at least one oxo, and furtheroptionally substituted,

or a pharmaceutically acceptable salt or solvate thereof.

In certain aspect, the disclosure provides a compound having thestructure of Formula (Ia):

wherein

R¹ is aryl, cycloalkyl, heterocyclyl, or heteroaryl, wherein the aryl,cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted;

R², R³, and R⁴ are each independently H, cyano, halo, ester, alkoxy,alkyl, heteroalkyl, cycloalkyl or, heterocyclyl, wherein the alkoxy,alkyl, heteroalkyl, cycloalkyl or, heterocyclyl is optionallysubstituted;

R⁵ is -L-R^(a), wherein L is a bond, alkyl, or heteroalkyl, and R^(a) isabsent, a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl,wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl isoptionally substituted;

R⁶ is H, alkyl, or heteroalkyl;

each R⁷ is independently H, cyano, halo, alkoxy, alkyl, heteroalkyl,cycloalkyl, or haloalkyl;

n is 0-6; and

R is alkyl or heteroalkyl substituted with at least one oxo, and furtheroptionally substituted,

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the alkyl or heteroalkyl of R is substituted withone or more substituent, each substituent independently selected fromthe group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether,disulfide, seleno, selenol, selenide, diselenide, sulfone, amide, halo,oxo, heterocyclyl, and cycloalkyl, wherein the heterocyclyl, andcycloalkyl is optionally substituted (e.g., with one or more substituentselected from the group consisting of alkyl, heteroalkyl, hydroxyl,thiol, thioether, disulfide, selenol, selenide, diselenide, sulfone,amide, halo and oxo).

In some embodiments, R is

X is —O— or a bond;

R⁸ is hydrogen, alkyl, heteroalkyl, or haloalkyl;

R⁹ is alkyl or heteroalkyl, the alkyl or heteroalkyl being optionallysubstituted,

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the alkyl or heteroalkyl of R⁹ is substituted withone or more substituent, each substituent independently selected fromthe group consisting of alkyl, heteroalkyl, hydroxyl, thiol, thioether,disulfide, seleno, selenol, selenide, diselenide, sulfone, amide, ester,carboxylic acid, halo, oxo, heterocyclyl, and cycloalkyl, wherein theheterocyclyl, and cycloalkyl is optionally substituted (e.g., with oneor more substituent selected from the group consisting of alkyl,heteroalkyl, hydroxyl, thiol, thioether, disulfide, selenol, sulfone,amide, ester halo and oxo).

In some embodiments, R⁶ is H. In some embodiments, R³ is H. In someembodiments, n is 0. In some embodiments, R¹ is optionally substitutedaryl, heteroaryl, cycloalkyl, or heterocyclyl. In some embodiments, R¹is heteroaryl. In some embodiments, R¹ is benzofuran. In someembodiments, R² and R⁴ are each independently H, halo, alkoxy, or alkyl.In some embodiments, R² and R⁴ are halo. In some embodiments, R² and R⁴are chloro. In some embodiments, R⁵ is optionally substituted aryl,heteroaryl, aryl-alkyl, or heteroaryl-alkyl. In some embodiments, R⁵ isoptionally substituted aryl-alkyl. In some embodiments, R⁵ issubstituted aryl-alkyl. In some embodiments, R⁵ is a sulfonylsubstituted aryl-alkyl.

In certain embodiments, the compound has the structure of Formula (Ib):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound has the structure of Formula (Ic):

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, X is —O— and R⁹ is C₁₋₆ alkyl—(CR^(d)R^(e))_(p)(C═O)O(C₁-C₆-alkyl), —(CR^(d)R^(e))_(p)carbocyclyl,—(CR^(d)R^(e))_(p)heterocyclyl, or

and

R^(d) and R^(e) are each independently H, halo, alkyl, alkoxy, hydroxyl,thioether, sulfide, thiol, disulfide, seleno, heteroalkyl, carbocyclyl,carbocyclylalkyl, carbocyclylalkoxy, carboxyl, heterocyclyl,heterocyclylalkyl, or heterocyclylalkoxy;

R¹⁰ is —(C═O)C₁₋₆ alkyl;

p is 1 to 6; and

wherein C₁₋₆ alkyl is optionally substituted with halo, alkyl,heteroalkyl, alkoxy hydroxyl, thiol, disulfide, selenide, diselenide,amide, heterocyclyl or heterocyclylalkyl.

In some embodiments, X is a bond and R⁹ is C₁₋₆ alkyl, heteroalkyl orheterocyclylalkyl wherein the C₁₋₆ alkyl may be linear or branched andis optionally substituted with halo, alkyl, heteroalkyl, alkoxyhydroxyl, thiol, disulfide, selenide, diselenide, amide, heterocyclyl orheterocyclylalkyl. In some embodiments, R⁹ is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, —CH₂OH, —CH(CH₃)OH,—CH₂(OCH₂CH₂)₄OH, —CH₂CH₂(OCH₂CH₂)₄OH,

In some embodiments, R⁹ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, CH₂OH,

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (I):

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (I′):

One embodiment provides a compound, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (II):

In one embodiment is provided a keratolytic conjugate, orpharmaceutically acceptable salt thereof, having a structure provided inTable 1.

TABLE 1 Chemistry Example Structure Name 1

1- ((isopropoxycarbonyl)oxy) ethyl (2R)-2-(2- (benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4- tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate 2

4-((2S)-3-(1- ((isopropoxycarbonyl)oxy) ethoxy)-2-((S)-4-methyl-2-(2-(o- tolyloxy)acetamido)pentan- amido)-3- oxopropyl)phenyl 4-carbamoylpiperidine-1- carboxylate 3

1- ((methoxycarbonyl)oxy) ethyl (2S)-2-(2- (benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4- tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate 4

1- ((ethoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro- 1,2,3,4- tetrahydroisoquinoline-6-carboxamido)-3-(3- (methylsulfonyl)phenyl) propanoate 5

1- ((isopropoxycarbonyl) oxy)ethyl (2S)-2-(2- (benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4- tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate 6

1-((tert- butoxycarbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro- 1,2,3,4- tetrahydroisoquinoline-6-carboxamido)-3-(3- (methylsulfonyl)phenyl) propanoate 7

1-(((((R)-1-methoxy-1- oxopropan-2- yl)oxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran- 6-carbonyl)-5,7-dichloro- 1,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3- (methylsulfonyl)phenyl)propanoate 8

1-(((((R)-1-ethoxy-1- oxopropan-2- yl)oxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran- 6-carbonyl)-5,7-dichloro- 1,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3- (methylsulfonyl)phenyl)propanoate 9

1-((((2,2-dimethyl-1,3- dioxan-5- yl)methoxy)carbonyl)oxy) ethyl(2S)-2-(2- (benzofuran-6-carbonyl)- 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3- (methylsulfonyl)phenyl)propanoate 10

1-(((3-hydroxy-2- (hydroxymethyl)propoxy) carbonyl)oxy)ethyl (2S)-2-(2-(benzofuran-6- carbonyl)-5,7-dichloro- 1,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3- (methylsulfonyl)phenyl)propanoate 11

2-((8S)-10-(2- (benzofuran-6-carbonyl)- 5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6- yl)-5-methyl-8-(3- (methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6- trioxa-9- azadecyl)propane-1,3- diyl diacetate 12

2-((8S)-10-(2- (benzofuran-6-carbonyl)- 5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6- yl)-5-methyl-8-(3- (methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6- trioxa-9- azadecyl)propane-1,3- diyl bis(2,2-dimethylpropanoate) 13

2-((8S)-10-(2- (benzofuran-6-carbonyl)- 5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6- yl)-5-methyl-8-(3- (methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6- trioxa-9- azadecyl)propane-1,3- diyl(2R,2'R)-bis(2- hydroxypropanoate) 14

1-acetoxyethyl (2S)-2-(2- (benzofuran-6-carbonyl)- 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3- (methylsulfonyl)phenyl)propanoate 15

1-(propionyloxy)ethyl (2S)-2-(2-(benzofuran-6- carbonyl)-5,7-dichloro-1,2,3,4- tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate 16

1-(isobutyryloxy)ethyl (2S)-2-(2-(benzofuran-6- carbonyl)-5,7-dichloro-1,2,3,4- tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate 17

1-(((S)-2-(2-(benzofuran- 6-carbonyl)-5,7-dichloro- 1,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3- (methylsulfonyl)phenyl)propanoyl)oxy)ethyl pivalate 18

1-(((R)-2- hydroxypropanoyl)oxy) ethyl (2S)-2-(2-(benzofuran-6-carbonyl)- 5,7-dichloro-1,2,3,4- tetrahydroisoquinoline-6-carboxamido)-3-(3- (methylsulfonyl)phenyl) propanoate 19

1-(2- hydroxyacetoxy)ethyl (2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro- 1,2,3,4- tetrahydroisoquinoline-6-carboxamido)-3-(3- (methylsulfonyl)phenyl) propanoate 20

1-(((S)-2-(2-(benzofuran- 6-carbonyl)-5,7-dichloro- 1,2,3,4-tetrahydroisoquinoline-6- carboxamido)-3-(3- (methylsulfonyl)phenyl)propanoyl)oxy)ethyl 5- ((R)-1,2-dithiolan-3- yl)pentanoate

Preparation of Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are optionally identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (contact theAmerican Chemical Society, Washington, D.C. for more details). Chemicalsthat are known but not commercially available in catalogs are optionallyprepared by custom chemical synthesis houses, where many of the standardchemical supply houses (e.g., those listed above) provide customsynthesis services. A reference for the preparation and selection ofpharmaceutical salts of the dual-acting meibomian gland dysfunctionpharmacological agent described herein is P. H. Stahl & C. G. Wermuth“Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta,Zurich, 2002.

Pharmaceutical Compositions

In some embodiments, the keratolytic conjugate described herein has astructure provided in any one of Formula (Ia), Formula (Ib), Formula(Ic), Formula (Id), Formula (I), or Formula (I′). In some embodiments,the keratolytic conjugate described herein has a structure provided inFormula (II). In some embodiments, the keratolytic conjugate describedherein has a structure provided in Formula (III). In certainembodiments, the keratolytic conjugates as described herein isadministered as a pure chemical. In other embodiments, the keratolyticconjugate described herein is combined with a pharmaceutically suitableor acceptable carrier (also referred to herein as a pharmaceuticallysuitable (or acceptable) excipient, physiologically suitable (oracceptable) excipient, or physiologically suitable (or acceptable)carrier) selected on the basis of a chosen route of administration andstandard pharmaceutical practice as described, for example, inRemington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

Provided herein is a pharmaceutical composition comprising at least onekeratolytic conjugate, or a stereoisomer, pharmaceutically acceptablesalt, hydrate, solvate, or N-oxide thereof, together with one or morepharmaceutically acceptable carriers. The carrier(s) (or excipient(s))is acceptable or suitable if the carrier is compatible with the otheringredients of the composition and not deleterious to the recipient(i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising anycompound provided herein, such as a compound of any one of Formula (Ia),Formula (Ib), Formula (Ic), Formula (Id), Formula (I), or Formula (I′),or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient. One embodiment provides apharmaceutical composition comprising any compound provided herein, suchas a compound of any one of Formula (II), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient. Another embodiment provides the pharmaceutical composition,wherein the pharmaceutical composition is suitable for ophthalmicadministration. Another embodiment provides the pharmaceuticalcomposition, wherein the pharmaceutical composition is suitable fortopical ophthalmic administration. In some embodiments, topicalophthalmic administration is administration in and/or around the eye,such as to the eyelid margin. In some embodiments, topical ophthalmicadministration is administration to the ocular surface and the innersurface to the eyelid.

One embodiment provides a pharmaceutical composition comprising acompound of Formula (II), or a pharmaceutically acceptable salt thereof,and at least one pharmaceutically acceptable excipient. Anotherembodiment provides the pharmaceutical composition, wherein thepharmaceutical composition is suitable for ophthalmic administration.Another embodiment provides the pharmaceutical composition, wherein thepharmaceutical composition is suitable for topical ophthalmicadministration. In some embodiments, topical ophthalmic administrationis administration in and/or around the eye, such as to the eyelidmargin. In some embodiments, topical ophthalmic administration isadministration to the ocular surface and the inner surface to theeyelid.

In certain embodiments, any compound provided herein, such as thekeratolytic conjugate as described by any one of Formula (Ia), Formula(Ib), Formula (Ic), Formula (Id), Formula (I), Formula (I′), Formula(II), or Formula (III) (or pharmaceutically acceptable salt thereof) issubstantially pure, in that it contains less than about 5%, or less thanabout 1%, or less than about 0.1%, of other organic small molecules,such as unreacted intermediates or synthesis by-products that arecreated, for example, in one or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract. Insome embodiments, suitable nontoxic solid carriers are used whichinclude, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

In some embodiments, the keratolytic conjugate as described by any oneof Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (I),Formula (I′), Formula (II), or Formula (III) is formulated as a solutionor suspension for topical administration to the eye.

In some embodiments, the keratolytic conjugate as described by any oneof Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (I),Formula (I′), Formula (II), or Formula (III) is formulated foradministration by injection. In some instances, the injectionformulation is an aqueous formulation. In some instances, the injectionformulation is a non-aqueous formulation. In some instances, theinjection formulation is an oil-based formulation, such as sesame oil,or the like.

The dose of the composition comprising at least one keratolyticconjugate as described herein differ, depending upon the patient's(e.g., human) condition, that is, general health status, age, and otherfactors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity). Optimal doses are generally determined usingexperimental models and/or clinical trials. The optimal dose dependsupon the body mass, weight, or blood volume of the patient.

In other embodiments, the topical compositions described herein arecombined with a pharmaceutically suitable or acceptable carrier (e.g., apharmaceutically suitable (or acceptable) excipient, physiologicallysuitable (or acceptable) excipient, or physiologically suitable (oracceptable) carrier). Exemplary excipients are described, for example,in Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

Methods of Treatment Utilizing Keratolytic Conjugates

One embodiment provides a method of treating an ophthalmic disease ordisorder in a patient in need of thereof, comprising administering tothe patient any compound provided herein, or a pharmaceuticallyacceptable salt thereof, or a (e.g., pharmaceutical) compositioncomprising any compound provided herein, or a pharmaceuticallyacceptable salt thereof, such as a compound of any one of Formula (Ia),Formula (Ib), Formula (Ic), Formula (Id), Formula (I), Formula (I′),Formula (II), or Formula (III). Another embodiment provides the methodwherein the pharmaceutical composition is in the form of a solution orsuspension suitable for topical ophthalmic administration. In someembodiments, topical ophthalmic administration is administration inand/or around the eye, such as to the eyelid margin. In someembodiments, topical ophthalmic administration is administration to theocular surface and the inner surface to the eyelid.

Another embodiment provides the method wherein the ophthalmic disease ordisorder is selected from dry eye, lid wiper epitheliopathy (LWE),contact lens discomfort (CLD), dry eye syndrome, evaporative dry eyesyndrome, aqueous deficiency dry eye syndrome, blepharitis, keratitis,meibomian gland dysfunction, conjunctivitis, lacrimal gland disorder,contact lens related conditions and inflammation of the anterior surfaceof the eye, infection of the anterior surface of the eye, and autoimmunedisorder of the anterior surface of the eye.

Described herein are methods for treating ocular surface disorders in apatient in need comprising topical administration of a keratolyticconjugate to the patient. There are two potential categories ofadministration. One occurs with the assistance of a health-careprovider: this category includes both acute and maintenance uses of thekeratolytic conjugate. An acute use, in one embodiment, requires astronger keratolytic conjugate (either in terms of concentration of theagent or the inherent activity of the agent). A maintenance use, in oneembodiment, allows for the use of lower concentrations of the agent, oragents with lower inherent activity. A maintenance use, in oneembodiment, involves a patient at a routine visit to the health careprovider. Both acute uses and maintenance uses optionally involve use ofan eye-protecting device or apparatus. In one embodiment, the acute useis performed by the health care provider, and the maintenance use isperformed by the patient or non-health care provider. The secondpotential category of administration does not occur with the activeassistance of a health care provider, but rather involves the patientapplying the keratolytic conjugate to his/her own eyelid margin. In oneembodiment, such administration occurs over an extended period of time;one way of describing this patient-administered multi-administrationmode is as a chronic use. In general, different or second formulationsof the keratolytic conjugate are recommended for chronic orpatient-administered uses. In one embodiment the different or secondformulation utilizes a lower concentration of the keratolytic conjugate.In another embodiment, the second or different formulation utilizes akeratolytic conjugate that has a lower activity than the firstformulation.

It should be understood that the present methods also include thephysical removal of the obstruction in the meibomian gland, followed bychronic and/or maintenance administration of the keratolytic conjugatedescribed herein.

One embodiment provides a method for treating meibomian glanddysfunction in a patient in need thereof, comprising topicallyadministering to the patient a composition comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier. In some embodiments, thetopical administration of the composition comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier results in enhanced meibumproduction.

In some embodiments, the topical administration of the compositioncomprising a therapeutically-effective amount of at least onekeratolytic conjugate in an ophthalmically-acceptable carrier occursuntil the keratinized obstruction is relieved. In some embodiments, thetopical administration of the composition comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier occurs periodically afterrelieving of the keratinized obstruction. In some embodiments, thetopical administration of the composition comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is a single administration. Insome embodiments, the topical administration of the compositioncomprising a therapeutically-effective amount of at least onekeratolytic conjugate in an ophthalmically-acceptable carrier is aperiodic administration. In some embodiments, the topical administrationof the composition comprising a therapeutically-effective amount of atleast one keratolytic conjugate in an ophthalmically-acceptable carrieroccurs once a day. In some embodiments, the topical administration ofthe composition comprising a therapeutically-effective amount of atleast one keratolytic conjugate in an ophthalmically-acceptable carrieroccurs twice a day. In some embodiments, the topical administration ofthe composition comprising a therapeutically-effective amount of atleast one keratolytic conjugate in an ophthalmically-acceptable carrieroccurs more than twice a day.

In some embodiments, the composition for topical administration,comprising a therapeutically-effective amount of at least onekeratolytic conjugate in an ophthalmically-acceptable carrier is asolution. In some embodiments, the composition for topicaladministration, comprising a therapeutically-effective amount of atleast one keratolytic conjugate in an ophthalmically-acceptable carrieris a solution suitable for topical administration as eye drops. In someembodiments, the composition for topical administration, comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is a gel, ocular insert, spray,or other topical ocular delivery method. In some embodiments, thecomposition for topical administration, comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is a semi-solid. In someembodiments, the composition for topical administration, comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is homogenous. In someembodiments, the composition for topical administration, comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is a dispersion. In someembodiments, the composition for topical administration, comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier is hydrophilic. In someembodiments, the composition for topical administration, comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier has an oleaginous base. In someembodiments, the composition for topical administration, comprising atherapeutically-effective amount of at least one keratolytic conjugatein an ophthalmically-acceptable carrier has at least oneophthalmically-acceptable excipient.

One embodiment provides a method for treating MGD in a patient in needthereof comprising topical administration of a composition comprising akeratolytic conjugate. In some embodiments, the topical administrationof the composition comprising a keratolytic conjugate occurs once aweek. In some embodiments, the topical administration of the compositioncomprising a keratolytic conjugate occurs twice a week. In someembodiments, the topical administration of the composition comprising akeratolytic conjugate occurs every other day. In some embodiments, thetopical administration of the composition comprising a keratolyticconjugate occurs every day. In some embodiments, the topicaladministration of the composition comprising a keratolytic conjugateoccurs several times a day.

In some embodiment, the method comprises treatment in an acute treatmentscenario. In another embodiment, the method comprises treatment of apatient naïve to treatment. In another embodiment, the method comprisestreatment in a chronic treatment scenario. In another embodiment, themethod comprises treatment in a maintenance therapy scenario. In anacute treatment scenario, the administered dosage of keratolyticconjugate maybe higher than the administered dosage of keratolyticconjugate employed in a chronic treatment scenario or a maintenancetherapy scenario. In an acute treatment scenario, the keratolyticconjugate maybe different from the keratolytic conjugate employed in achronic treatment scenario. In some embodiments, the course of therapybegins in the initial phase of therapy as an acute treatment scenarioand later transitions into a chronic treatment scenario or a maintenancetherapy scenario. In some embodiments, the meibomian gland openingpharmacological agent administered in the acute treatment scenario is akeratolytic agent and/or keratoplastic agent, and the pharmacologicalagent administered in the chronic treatment scenario or a maintenancetherapy scenario is a keratolytic conjugate.

In certain clinical presentations, patients may require an initialtreatment administered by a physician or healthcare professional, toinitially open the blockage of the meibomiam gland, such as by placing amore highly concentrated formulation of one of the keratolyticconjugates described herein. In the event the higher concentrationformulations are required, the application thereof may require ocularshielding or other activity to minimize the impact of irritation ordisruption of the ocular surface or surrounding tissues. Following sucha procedure, a patient may be given a different formulation ofkeratolytic conjugate to take home to apply periodically to the lidmargin to maintain the patency of the meibomiam gland. Such applicationmay occur twice daily, once a day, weekly or monthly, depending on theformulation activity and the desired product profile of the therapy.

One aspect of the methods of treatment described herein is the locationof the topical administration of the composition. In one embodiment, thecomposition comprising a keratolytic conjugate is administered such thatno irritation to eye occurs. In one embodiment, the compositioncomprising a keratolytic conjugate is administered to the eye lidmargin.

One additional embodiment of the methods of treatment described hereinis the use of a protective element provided to the eye to avoidirritation to the eye. Although the formulations described herein aregenerally non-irritating, in some embodiments (e.g., high concentrationof agent or when used on a sensitive eye) a protective element providesan additional layer of safety and comfort for the patient. In oneembodiment, the composition comprising a keratolytic conjugate isadministered while an eye shield is placed on the eye to reduce contactof the pharmacological agent with the cornea and/or conjunctiva suchthat reduced irritation to eye occurs. In some embodiments, the eyeshield is a contact lens or an eye covering. In some embodiments, theeye covering comprises a self-adhesive. In one embodiment, thecomposition comprising a keratolytic conjugate is administered while thelid is pulled away from the globe to reduce contact of thepharmacological agent with the cornea and/or conjunctiva such thatreduced irritation to eye occurs.

EXAMPLES I. Chemical Synthesis

Solvents, reagents and starting materials were purchased from commercialvendors and used as received unless otherwise described. All reactionswere performed at room temperature unless otherwise stated. Startingmaterials were purchased from commercial sources or synthesisedaccording to the methods described herein or using literatureprocedures.

Abbreviations

The following abbreviations are used in the Examples and other parts ofthe description:

-   AcOH: acetic acid-   CD₂Cl₂: deuterated dichloromethane-   CDCl₃: deuterated chloroform-   COMU:    (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium    hexafluorophosphate-   DCC: dicyclohexyl carbodiimide-   DCM: dichloromethane-   DIPEA: N,N-diisopropylethylamine-   DMF: N,N-Dimethylformamide-   DMSO-D6: Dimethyl sulfoxide-d₆-   EtOAc: Ethyl acetate-   EtOH: ethanol-   HCl: hydrochloric acid-   H₂O: Water-   HPLC: High performance liquid chromatography-   KHSO₄: potassium bisulfate-   MeCN: Acetonitrile-   MeOH: Methanol-   MgSO₄: Magnesium sulfate-   mins: Minutes-   N₂: nitrogen-   NaHCO₃: sodium bicarbonate-   NH₄Cl: ammonium chloride-   Rt: retention time-   r.t.: room temperature-   sat.: saturated-   TFA: trifluoroacetic acid-   THF: tetrahydrofuran

Analytical Methods

Method A: Phenomenex Gemini C18 5 μm, 150×4.6 mm; A=water+0.1% formicacid; B=MeOH; 40° C.; % B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min95%, 10.1 min 5%, 13.0 min 5%; 1.5 mL/min.

Method B: Phenomenex Luna C18 (2) 3 μm, 50×4.6 mm; A=water+0.1% formicacid; B=MeOH+0.1% formic acid; 45° C.; % B: 0.0 min 5%, 1.0 min 37.5%,3.0 min 95%, 3.5 min 95%, 3.51 min 5%, 4.0 min 5%; 2.25 mL/min.

Method C: Phenomenex Luna C18 (2) 5 μm, 150×4.6 mm; A=water+0.1% formicacid; B=MeCN; 40° C.; % B: 0.0 min 5%, 0.5 min 5%, 7.5 min 95%, 10.0 min95%, 10.1 min 5%, 13.0 min 5%; 1.50 mL/min.

Method D: Phenomenex Luna C18 (2) 3 μm, 50×4.6 mm; A=water pH 9(ammonium bicarbonate 10 mM); B=MeOH; 45° C.; % B: 0.0 min 5%, 1.0 min37.5%, 3.0 min 95%, 3.5 min 95%, 3.51 5%, 4.0 min 5%; 2.25 mL/min.

Method E: Waters Sunfire C18 3.5 μm, 50×4.6 mm; A=water+0.1% formicacid; B=MeCN; 40° C.; % B: 0.0 min 5%, 1.0 min 37.5%, 3.0 min 95%, 3.5min 95%, 3.51 min 5%, 4.0 min 5%; 2.25 m/min.

Method F: Phenomenex Gemini NX C18 5 μm, 150×4.6 mm; A=water+0.1% formicacid; B=MeOH+0.1% formic acid; 40° C.; % B: 0.0 min 5%, 0.5 min 5%, 7.5min 95%, 10.0 min 95%, 10.1 min 5%, 13.0 min 5%; 1.5 mL/min.

Chemical Synthesis Example 1 1-((Isopropoxycarbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

To a stirred solution of Lifitegrast (250 mg, 0.410 mmol) in anhydrousDMF (5 mL) was added 1-chloroethyl isopropyl carbonate (81.2 mg, 0.490mmol) followed by potassium carbonate (73.0 mg, 0.530 mmol) and themixture stirred at 55° C. for 2 hours. The mixture was diluted withEtOAc and washed successively with water followed by sat. brinesolution. The organic phase was dried (MgSO₄) and the solvent evaporatedin vacuo. The residue was dissolved in DMSO and the product purified byreversed-phase preparative HPLC. Fractions containing product werecombined and concentrated in vacuo to approximately 1/5 of the volume.The mixture was diluted with EtOAc and washed successively with waterfollowed by sat. brine solution. The organic phase was dried (MgSO₄),filtered and the solvent evaporated in vacuo. The residue was dissolvedin 1:1 MeCN—H₂O and the solution frozen. The solvent was evaporated bylyophilisation to reveal the title compound as an off-white solid (72mg, 24%). LCMS (Method A): Rt=7.87 mins; [M+H]+=745.3. ¹H-NMR (400 MHz,CD₂Cl₂) δ 7.78-7.91 (m, 2H), 7.76 (d, J=2.1 Hz, 1H), 7.67 (d, J=7.8 Hz,1H), 7.57-7.64 (m, 2H), 7.49-7.56 (m, 1H), 7.31 (d, J=7.8 Hz, 1H),6.83-6.93 (m, 1H), 6.77 (td, J=11.1, 5.5 Hz, 1H), 6.32 (dd, J=20.4, 8.5Hz, 1H), 5.17-5.28 (m, 1H), 4.51-4.99 (m, 3H), 3.78 (s, 2H), 3.17-3.49(m, 2H), 2.98-3.07 (m, 3H), 2.87 (s, 2H), 1.49-1.56 (m, 3H), 1.25-1.34(m, 6H).

Chemical Synthesis Example 24-((2S)-3-(1-((isopropoxycarbonyl)oxy)ethoxy)-2-((S)-4-methyl-2-(2-(o-tolyloxy)acetamido)pentanamido)-3-oxopropyl)phenyl4-carbamoylpiperidine-1-carboxylate

3-[4-(4-carbamoylpiperidine-1-carbonyl)oxyphenyl]-2-[[(2S)-4-methyl-2-[[2-(2-methylphenoxy)acetyl]amino]pentanoyl]amino]propanoicacid (80 mg, 0.134 mmol) was dissolved in anhydrousN,N-dimethylformamide (5.0 mL). 1-Chloroethyl isopropyl carbonate (50mL, 0.327 mmol) was added and the mixture stirred at 60° C. for 24hours. N,N-Diisopropylethylamine (80 mL, 0.459 mmol) and 1-chloroethylisopropyl carbonate (50 mL, 0.327 mmol) were added and the mixturestirred at 60° C. for 2 hours. The solvent was evaporated in vacuo, andthe residue partitioned between EtOAc (40 mL) and sat. NaHCO_(3(aq)) (20mL). The layers were separated and the organic phase washed with sat.brine solution (20 mL), dried (MgSO₄), filtered, and the solventevaporated in vacuo. The crude product was purified by flashchromatography (Biotage SP1; 10 g SNAP cartridge) eluting with EtOAc→20%acetone-EtOAc to yield[4-[3-(1-isopropoxycarbonyloxyethoxy)-2-[[(2S)-4-methyl-2-[[2-(2-methylphenoxy)acetyl]amino]pentanoyl]amino]-3-oxo-propyl]phenyl]4-carbamoylpiperidine-1-carboxylate (58 mg, 60%) as an off-white solid.LCMS (Method F): Rt=8.36 mins (98.1%) [M+H]+=727.6.

Chemical Synthesis Example 3 1-((tert-Butoxycarbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Method A:

To a mixture of Lifitegrast (20 mg, 0.0300 mmol), DIPEA (11 mL, 0.0650mmol) and DMF (1 mL), under an atmosphere of N₂, was added tert-butyl1-chloroethyl carbonate (7.04 mg, 0.0400 mmol). The reaction mixture wasstirred at 60° C. for 48 hours. tert-Butyl 1-chloroethyl carbonate (5.9mg, 0.033 mmol) and DIPEA (8.9 μL, 0.065 mmol) were added and thereaction mixture stirred at 60° C. for 4 hours. Potassium iodide (5.4mg, 0.0325 mmol) was added and the reaction mixture stirred at 60° C.for 72 hours. The reaction mixture was diluted with EtOAc (10 mL), andthe solution washed successively with H₂O (2×5 mL) and sat. brinesolution (5 mL). The organic phase was dried (MgSO₄), filtered and thesolvent evaporated in vacuo. The crude product was then purified bypreparative reversed-phase HPLC.

Method B:

A mixture of Lifitegrast (15 mg, 0.0244 mmol), tert-butyl 1-chloroethylcarbonate (8.8 mg, 0.0487 mmol) and cesium carbonate (8.0 mg, 0.0244mmol) were dissolved in DMF (1 mL) and the mixture stirred at r.t. for72 hours. The reaction mixture was passed through a syringe filter andthe crude product purified by preparative reversed-phase HPLC.

Method C:

A mixture of Lifitegrast (15 mg, 0.0244 mmol), tert-butyl 1-chloroethylcarbonate (8.8 mg, 0.0487 mmol), cesium carbonate (8.0 mg, 0.0244 mmol)and potassium iodide (2.0 mg, 0.0122 mmol) were dissolved in DMF (1 mL)and the mixture stirred at r.t. for 72 hours. The reaction mixture waspassed through a syringe filter and the crude product purified bypreparative reversed-phase HPLC.

Method D:

The three individual samples from methods A, B & C were combined (assolutions in MeOH) and the solvent evaporated in vacuo. The crudeproduct was purified by preparative reversed-phase HPLC, desiredfractions combined, and the solvent evaporated in vacuo. The residue wasdissolved in 1:1 MeCN—H₂O (2 mL) and the solution frozen. The solventwas evaporated in vacuo (lyophilisation) to yield1-((tert-butoxycarbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(10.2 mg, 16% (combined yield)) as a white solid. LCMS (Method F):Rt=8.01 min; [M+H]+=759.5 ¹H-NMR (400 MHz, DMSO-d6) δ 9.15-9.20 (1H, m),8.12 (1H, d, J=2.3 Hz), 7.87 (1H, br s), 7.66-7.78 (4H, m), 7.53-7.58(1H, m), 7.10-7.50 (2H, br m), 7.03-7.04 (1H, m), 6.62-6.69 (1H, m),4.85-4.93 (1H, m), 4.60-4.84 (2H, br s), 3.52-3.94 (2H, m), 3.25-3.30(1H, m, partially obscured by H₂O peak), 3.13-3.15 (3H, m), 2.98-3.05(1H, m), 2.76 (2H, br s), 1.39-1.46 (12H, m).

Chemical Synthesis Example 4 1-Chloroethyl((2,2-dimethyl-1,3-dioxan-5-yl)methyl) carbonate

To an ice-cold solution of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (0.40mL, 2.78 mmol) and pyridine (0.45 mL, 5.56 mmol) in DCM (2 mL) was addeddropwise over 1 minute 1-chloroethyl chloroformate (0.30 mL, 2.78 mmol)and the mixture stirred at r.t. for 4 hours. The reaction mixture waspartitioned between DCM (10 mL) and H₂O (10 mL) and the organic phaseseparated (phase separator). The solvent was evaporated in vacuo and thecrude product purified by flash chromatography eluting withisohexane→EtOAc to yield 1-chloroethyl((2,2-dimethyl-1,3-dioxan-5-yl)methyl) carbonate as a yellow/green oil(508 mg, 72%). ¹H-NMR (400 MHz, DMSO-d6) δ 6.47 (1H, q, J=5.8 Hz), 4.21(2H, d, J=7.3 Hz), 3.88 (2H, dd, J=11.7, 3.9 Hz), 3.60 (2H, J=5.8 Hz,2H), 1.89-1.95 (1H, m), 1.73 (3H, d, J=6.0 Hz), 1.30 (3H, s), 1.26 (3H,s).

Chemical Synthesis Example 51-((((2,2-Dimethyl-1,3-dioxan-5-yl)methoxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

A mixture of Lifitegrast (100 mg, 0.162 mmol), 1-chloroethyl(2,2-dimethyl-1,3-dioxan-5-yl)methyl carbonate (123 mg, 0.487 mmol) andDIPEA (110 mL, 0.650 mmol) were dissolved in DMF (1 mL). The mixture wasstirred under N₂ at 60° C. for 18 hours. The reaction mixture wasdiluted with EtOAc (25 mL) and washed successively with H₂O (10 mL),sat. NaHCO_(3(aq)) (10 mL) and sat. brine solution (10 mL). The organicphase was dried (MgSO₄), filtered and the solvent evaporated in vacuo.Three purification strategies were then attempted:

Purification Method A:

Approximately one quarter of the crude material was dissolved in MeCN (2mL) and purified by preparative reversed-phase HPLC. Desired fractionswere combined and the solvent evaporated in vacuo. The residue wasdissolved in a 1:1 MeCN—H₂O (2 mL) and the solution frozen. The solventwas evaporated in vacuo (lyophilisation).

Purification Method B:

Approximately one quarter of the crude material was dissolved in MeCN (2mL) and purified by preparative reversed-phase HPLC. Desired fractionswere combined and extracted with EtOAc (2×50 mL). The combined organicswere washed successively with H₂O (50 mL) and sat. brine solution (50mL), dried (MgSO₄), filtered and the solvent evaporated in vacuo. Theresidue was dissolved in 1:1 MeCN—H₂O (2 mL) and the solution frozen.The solvent was evaporated in vacuo (lyophilisation) to yield1-((((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(10.3 mg, 8%) as a white solid.

Purification Method C:

The remaining crude material plus the material isolated fromPurification Method A were combined as solutions in MeCN (2 mL) thenpurified by preparative reversed-phase HPLC. Desired fractions werecombined and extracted with EtOAc (2×50 mL). The combined organics werewashed with sat. brine solution (50 mL), dried (MgSO₄), filtered, andthe solvent evaporated in vacuo. The residue was dissolved in a 1:1MeCN—H₂O (2 mL) and the solution frozen. The solvent was evaporated invacuo (lyophilisation) to yield1-((((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoateas an off-white sticky solid (39.1 mg, 29%). LCMS (Method F): Rt=7.78min; [M+H]+=831.6. ¹H-NMR (400 MHz, DMSO-d6) δ 9.18 (1H, d, J=7.8 Hz),8.12 (1H, d, J=2.3 Hz), 7.88 (1H, br s), 7.65-7.78 (4H, m), 7.55 (1H,td, J=7.8, 1.8 Hz), 7.10-7.50 (2H, br m), 7.03-7.04 (1H, m), 6.68-6.73(1H, m), 4.87-4.95 (1H, m), 4.61-4.81 (2H, br s), 4.19 (2H, d, J=7.3Hz), 3.50-4.00 (6H, br m), 3.27-3.31 (1H, m, partially obscured by H₂0peak), 3.13-3.14 (3H, m), 3.00-3.06 (1H, m), 2.76 (2H, br s), 1.89-1.96(1H, br m), 1.48 (1.5H, d, J=5.5 Hz), 1.44 (1.5H, d, J=5.5 Hz), 1.31(3H, s), 1.27 (3H, s).

Chemical Synthesis Example 62-((((1-Chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diylbis(2,2-dimethylpropanoate)

A solution of 1-chloroethyl chloroformate (56 mL, 0.519 mmol) in DCM (2mL) was placed under an atmosphere of nitrogen and cooled to 0° C.Pyridine (56 mL, 0.693 mmol) was added followed by[2-(2,2-dimethylpropanoyloxymethyl)-3-hydroxy-propyl]2,2-dimethylpropanoate (200 mL, 0.346 mmol) and the mixture stirred atr.t. for 3 hours. 1-Chloroethyl chloroformate (56 mL, 0.519 mmol) andpyridine (56 mL, 0.693 mmol) were added and the mixture stirred at r.t.for 1 hour. The reaction mixture was partitioned between DCM (10 mL) andH₂O (10 mL) and the layers separated (phase separator). The solvent wasevaporated in vacuo and the residue purified by flash chromatography(Biotage SP1; 10 g cartridge) eluting with isohexane→40% EtOAc-isohexaneto yield 2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diylbis(2,2-dimethylpropanoate) (91 mg, 69%) as a colourless oil. ¹H-NMR(400 MHz, CDCl₃) δ 6.40 (1H, q, J=5.8 Hz), 4.24-4.31 (2H, m), 4.06-4.18(4H, m), 2.43-2.52 (1H, m), 1.82 (3H, d, J=5.5 Hz), 1.19 (18H, s).

Chemical Synthesis Example 72-((8S)-10-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diylbis(2,2-dimethylpropanoate)

A mixture of Lifitegrast (145 mg, 0.236 mmol),[2-(1-chloroethoxycarbonyloxymethyl)-3-(2,2-dimethylpropanoyloxy)propyl]2,2-dimethylpropanoate (90 mg, 0.236 mmol), DIPEA (82 mL, 0.473 mmol)and DMF (1 mL) were heated in a sealed vial at 60° C. The crude productwas purified by preparative reversed-phase HPLC. Desired fractions werecombined, and the solvents evaporated in vacuo. The residue wasdissolved in 1.1 MeCN—H₂O (3 mL) and the solution frozen. The solventwas evaporated in vacuo (lyophilisation) to yield2-((8S)-10-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diylbis(2,2-dimethylpropanoate) (81.1 mg, 36%) as a white solid. LCMS(Method F): Rt=8.54 min; [M+H]+=960.1. ¹H-NMR (400 MHz, DMSO-d6) δ 9.16(1H, d, J=7.8 Hz), 8.11 (1H, d, J=2.3 Hz), 7.87 (1H, br s), 7.66-7.77(4H, m), 7.53-7.57 (1H, m), 7.10-7.50 (2H, br m), 7.03-7.04 (1H, m),6.68-6.74 (1H, m), 4.86-4.94 (1H, m), 4.72 (2H, br s), 4.15-4.26 (2H,m), 4.02-4.11 (4H, m), 3.50-3.90 (2H, br s), 3.26-3.29 (1H, m, partiallyobscured by H₂O peak), 3.13-3.14 (3H, m), 2.98-3.07 (1H, m), 2.76 (2H,br s), 2.40-2.47 (1H, m), 1.48 (1.5H, d, J=5.3 Hz), 1.44 (1.5H, d, J=5.3Hz), 1.10-1.11 (18H, m).

Chemical Synthesis Example 81-(((3-Hydroxy-2-(hydroxymethyl)propoxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

To a solution of1-((((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(36 mg, 0.0433 mmol) in THF (1 mL) was added 2M HCl_((aq)) (0.50 mL,1.00 mmol) and the mixture stirred at r.t. for 30 minutes. The reactionmixture was diluted with water (10 mL) and the solution extracted withEtOAc (2×10 mL). The combined organics were washed successively withsat. NaHCO_(3(aq)) (10 mL), water (10 mL) and sat. brine solution (10mL). The organic phase was dried (MgSO₄), filtered and the solventevaporated in vacuo. The crude product was purified by purified bypreparative reversed-phase HPLC. Desired fractions were combined andextracted with EtOAc (2×50 mL). The combined organics were washed withsat. brine solution (50 mL), dried (MgSO₄), filtered and the solventevaporated in vacuo. The residue was dissolved in 1:1 MeCN—H₂O (2 mL)and the solution frozen. The solvent was evaporated in vacuo(lyophilisation) to yield1-(((3-hydroxy-2-(hydroxymethyl)propoxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(9.5 mg, 28%) as a white solid. LCMS (Method F): Rt=7.14 min;[M+H]+=791.5. ¹H-NMR (400 MHz, DMSO-d6) δ 9.16-9.21 (1H, m), 8.11-8.12(1H, m), 7.88 (1H, br s), 7.66-7.78 (4H, m), 7.53-7.58 (1H, m),7.10-7.50 (2H, br m), 7.03-7.04 (1H, m), 6.67-6.73 (1H, m), 4.87-4.93(1H, m), 4.73 (2H, br s), 4.54-4.57 (2H, m), 4.09-4.18 (2H, m),3.54-3.94 (2H, br m), 3.36-3.47 (4H, m), 3.27-3.31 (1H, m, partiallyobscured by H₂O peak), 3.13-3.15 (3H, m), 2.99-3.06 (1H, m), 2.76 (2H,br s), 1.82-1.89 (1H, m), 1.48 (1.5H, d, J=5.3 Hz), 1.44 (1.5H, d, J=5.3Hz).

Chemical Synthesis Example 92-((((1-Chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diyl Diacetate

A solution of 1-chloroethyl chloroformate (53 mL, 0.494 mmol) in DCM (2mL) was placed under an atmosphere of N₂ and cooled to 0° C. Pyridine(60 mL, 0.741 mmol) was added followed by[2-(acetoxymethyl)-3-hydroxy-propyl] acetate (200 mL, 0.247 mmol). Themixture was stirred at 0° C. for 6.5 hours. Pyridine (20 ml, 0.250 mmol)and 1-chloroethyl chloroformate (26 mL, 0.250 mmol) were added and themixture stirred at 0° C. for 90 minutes. 1-Chloroethyl chloroformate (26ml, 0.250 mmol) was added and the mixture stirred at 0° C. for 90minutes. The mixture was diluted with DCM (10 mL) and H₂O (10 mL). Thelayers were separated (phase separator) and the organic phase evaporatedin vacuo. The crude product was purified by flash chromatography(Biotage SP1; 10 g cartridge) eluting with isohexane→40% EtOac-isohexaneyield 2-((((1-chloroethoxy)carbonyl)oxy)methyl)propane-1,3-diyldiacetate (34 mg, 46%) as a colourless oil. ¹H-NMR (400 MHz, CDCl₃) δ6.39 (1H, q, J=5.8 Hz), 4.27 (2H, d, J=6.0 Hz), 4.09-4.17 (4H, m),2.38-2.47 (1H, m), 2.05 (6H, s), 1.81 (3H, d, J=5.5 Hz).

Chemical Synthesis Example 102-((8S)-10-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diylDiacetate

A mixture of [2-(acetoxymethyl)-3-(1-chloroethoxycarbonyloxy)propyl]acetate (34 mg, 0.115 mmol), Lifitegrast (71 mg, 0.115 mmol) and DIPEA(40 mL, 0.229 mmol) were dissolved in DMF (1 mL) and the mixture stirredat 60° C. for 72 hours. The crude product was purified by purified bypreparative reversed-phase HPLC. Desired fractions were combined, andthe solvent evaporated in vacuo. The residue was dissolved in 1:1MeCN—H₂O (3 mL) and the solution frozen. The solvent was evaporated invacuo (lyophilisation) to yield2-((8S)-10-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyldiacetate (34.4 mg, 34%) as an off-white solid. LCMS (Method F): Rt=7.66min; [M+H]+=875.5. ¹H-NMR (400 MHz, DMSO-d6) δ 9.18 (1H, d, J=7.8 Hz),8.12 (1H, d, J=2.3 Hz), 7.88 (1H, br s), 7.66-7.77 (4H, m), 7.53-7.58(1H, m), 7.15-7.50 (2H, br m), 7.03-7.04 (1H, m), 6.67-6.73 (1H, m),4.87-4.94 (1H, m), 4.73 (2H, br s), 4.14-4.23 (2H, m), 4.05 (4H, d,J=6.0 Hz), 3.55-3.90 (2H, br m), 3.27-3.31 (1H, m, partially obscured byH₂O peak), 3.13-3.14 (3H, m), 2.99-3.06 (1H, m), 2.76 (2H, br s),2.35-2.41 (1H, m), 1.98-2.00 (6H, m), 1.48 (1.5H, d, J=5.5 Hz), 1.44(1.5H, d, J=5.5 Hz).

Chemical Synthesis Example 11 1-Acetoxyethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Lifitegrast (60 mg, 0.0975 mmol), 1-chloroethyl acetate (18 mg, 0.147mmol) and DIPEA (34 mL, 0.195 mmol) in DMF (0.90 mL) were heated at 60°C. in a sealed tube for 16 hours. The crude product was purifiedpreparative reversed-phase HPLC to yield 1-acetoxyethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(28 mg, 39%) as an off-white solid. LCMS (Method F): Rt=7.45 min;[M+H]+=701.5. ¹H-NMR (400 MHz, DMSO-d6) δ 9.13-9.16 (1H, m), 8.09 (1H,d, J=2.3 Hz), 7.84 (1H, s), 7.63-7.74 (4H, m), 7.51-7.55 (1H, m), 7.28(2H, s), 7.00-7.01 (1H, m), 6.74-6.79 (1H, m), 4.82-4.88 (1H, m), 4.70(2H, br s), 3.61 (2H, br s), 3.23-3.29 (1H, m, partially obscured by H₂Opeak), 3.11 (3H, m), 2.94-3.03 (1H, m), 2.73 (2H, br s), 2.01 (3H, s),1.39 (3H, dd, J=17.9, 5.5 Hz).

Chemical Synthesis Example 12 1-(Isobutyryloxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Lifitegrast (60 mg, 0.0975 mmol), 1-chloroethyl 2-methylpropanoate (22mg, 0.146 mmol) and DIPEA (34 mL, 0.195 mmol) in DMF (0.90 mL) wereheated at 60° C. in a sealed tube for 16 hours. The crude product waspurified by preparative reversed-phase HPLC to yield1-(isobutyryloxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(46 mg, 61%) as a brown solid. LCMS (Method F): Rt=7.88 min;[M+H]+=729.5. ¹H-NMR (400 MHz, DMSO-d6) δ 9.13-9.17 (1H, m), 8.09 (1H,d, J=2.3 Hz), 7.84 (1H, s), 7.63-7.75 (4H, m), 7.50-7.55 (1H, m),7.27-7.29 (2H, m), 7.01 (1H, m), 6.72-6.79 (1H, m), 4.80-4.89 (1H, m),4.70 (2H, br s), 3.62 (2H, br s), 3.21-3.26 (1H, m), 3.11 (3H, d, J=3.4Hz), 2.94-3.03 (1H, m), 2.73 (2H, br s), 2.48-2.53 (1H, m), 1.39 (3H,dd, J=22.9, 5.5 Hz), 1.04 (6H, dd, J=7.1, 2.1 Hz).

Chemical Synthesis Example 13 Methyl(2R)-2-(((I-chloroethoxy)carbonyl)oxy)propanoate

To a solution of 1-chloroethyl chloroformate (339 μL, 3.14 mmol) andpyridine (381 μL, 4.71 mmol) in DCM (10 mL) at 0° C. under N₂ was added(R)-methyl 2-hydroxypropanoate (150 μL, 1.57 mmol) in DCM (2 mL)dropwise over 5 mins. The reaction mixture was stirred at r.t. for 16hours *. The mixture was diluted with DCM (30 mL) and the solutionwashed with H₂O (30 mL). The organic phase was separated (phaseseparator) and the solvent evaporated in vacuo. The crude product waspurified by flash chromatography eluting with isohexane→15%EtOAc-isohexane to yield methyl(2R)-2-(((1-chloroethoxy)carbonyl)oxy)propanoate (275 mg, 75%) as acolourless oil. ¹H-NMR (400 MHz, CDCl₃) δ 6.38-6.43 (1H, m), 5.04-5.10(1H, m), 3.77 (3H, m), 1.84 (3H, dd, J=6.0, 4.1 Hz), 1.54-1.56 (3H, m).

* Alternatively, the reaction mixture may be stirred at 0° C.→r.t. forup to 40 hours with additional equivalents of chloroformate (up to 0.54)added portion wise at irregular intervals over the course of thereaction to ensure almost complete conversion of the starting material.

Chemical Synthesis Example 141-(((((R)-1-Methoxy-1-oxopropan-2-yl)oxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Lifitegrast (60 mg, 0.0975 mmol), methyl(2R)-2-(((1-chloroethoxy)carbonyl)oxy)propanoate (34 mg, 0.146 mmol) andDIPEA (34 mL, 0.195 mmol) in DMF (0.90 mL) were heated in a sealed tubeat 60° C. for 16 hours *. The crude product was purified by preparativereversed-phase HPLC ** to yield1-(((((R)-1-methoxy-1-oxopropan-2-yl)oxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(30 mg, 37%) as an off-white solid. LCMS (Method F): Rt=7.62 min;[M+H]+=789.5. ¹H-NMR (400 MHz, DMSO-d6) δ 9.14-9.21 (1H, m), 8.08 (1H,d, J=1.8 Hz), 7.85-7.89 (1H, m), 7.63-7.74 (4H, m), 7.50-7.55 (1H, m),7.28 (2H, br s), 7.00-7.01 (1H, m), 6.64-6.70 (1H, m), 4.97-5.04 (1H,m), 4.82-4.90 (1H, m), 4.64 (2H, br s), 3.64-3.66 (5H, m), 3.21-3.26(1H, m), 3.11 (3H, m), 2.96-3.07 (1H, m), 2.73 (2H, br s), 1.39-1.48(6H, m).

* Alternatively, the mixture may be stirred under N₂ for up to 18 hoursat 60° C.

** Additionally, fractions containing desired product may be combinedand the solution frozen. The solvent may be evaporated in vacuo(lyophilisation).

Chemical Synthesis Example 15

The following compound was synthesized via an analogous method to thatdescribed for1-(((((R)-1-Methoxy-1-oxopropan-2-yl)oxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate:

Structure Analytical Data

LCMS (QC Method C): Rt = 7.36 mins; [M + H]+ = 803.2

Chemical Synthesis Example 16 (R)-2-(((Allyloxy)carbonyl)oxy)propanoicAcid

A solution of methyl (R)-2-(((allyloxy)carbonyl)oxy)propanoate (1.00 g,5.05 mmol) in THE (1 mL) and H₂O (1 mL) was cooled to 0° C. Lithiumhydroxide monohydrate (254 mg, 6.06 mmol) was added and the reactionmixture stirred at 0° C. for 3 hours. Lithium hydroxide monohydrate (254mg, 6.06 mmol) was added and the reaction mixture stirred at r.t. for 23hours. Lithium hydroxide monohydrate (254 mg, 6.06 mmol) and methanol (2mL) were added and the mixture stirred at r.t. for 90 minutes. Lithiumhydroxide monohydrate (254 mg, 6.06 mmol) was added and the reactionmixture heated at 40° C. for 90 minutes. The solvent was evaporated invacuo to a volume ˜2 mL and cooled to 0° C. The solution was acidifiedto pH1 with 1M HCl, diluted with H₂O (10 mL) and extracted with EtOAc(2×10 mL). The combined organics were washed with sat. brine solution(10 mL), dried (MgSO₄), filtered and the solvent evaporated in vacuo toyield (R)-2-(((allyloxy)carbonyl)oxy)propanoic acid (412 mg, 47%) as acolourless oil. ¹H-NMR (400 MHz, CDCl₃) δ 5.88-5.97 (1H, m), 5.34-5.40(1H, m), 5.25-5.30 (1H, m), 5.05 (1H, q, J=7.2 Hz), 4.66 (2H, td, J=3.4,1.8 Hz), 1.58 (3H, d, J=6.9 Hz).

Chemical Synthesis Example 172-((8S)-10-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl(2R,2′R)-bis(2-(((allyloxy)carbonyl)oxy)propanoate)

A solution of (R)-2-(((allyloxy)carbonyl)oxy)propanoic acid (81 mg,0.467 mmol), COMU (200 mg, 0.467 mmol) and DIPEA (110 mL, 0.654 mmol) inDCM (3 ml) were stirred at r.t. for 10 minutes. A solution of1-(((3-hydroxy-2-(hydroxymethyl)propoxy)carbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(74 mg, 0.0935 mmol) in DCM (2 mL) was added and the mixture stirred atr.t. for 18 hours. The solvent was evaporated in vacuo and the residuedissolved in EtOAc (30 mL). The solution was washed successively withsat. NH₄Cl_((aq)) (30 mL), H₂O (30 mL) and sat. brine solution (30 mL).The organic phase was dried (MgSO₄), filtered and the solvent evaporatedin vacuo. The crude product was purified by preparative reversed-phaseHPLC to yield2-((8S)-10-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl(2R,2′R)-bis(2-(((allyloxy)carbonyl)oxy)propanoate) (10 mg, 10%) as awhite solid. LCMS (Method D): Rt=3.34 min; [M+H]+=1103.8.

Chemical Synthesis Example 18(3R)-1-Hydroxy-7-((((R)-2-hydroxypropanoyl)oxy)methyl)-3-methyl-1,4,10-trioxo-2,5,9,11-tetraoxatridecan-12-yl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

A solution of2-((8S)-10-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)-5-methyl-8-(3-(methylsulfonyl)benzyl)-3,7,10-trioxo-2,4,6-trioxa-9-azadecyl)propane-1,3-diyl(2R,2′R)-bis(2-(((allyloxy)carbonyl)oxy)propanoate) (13 mg, 0.0113 mmol)in DCM (2 mL) was stirred under N₂. Phenylsilane (5.6 mL, 0.0453 mmol)and tetrakis(triphenylphosphine)palladium(O) (1.3 mg, 0.00113 mmol) wereadded and the mixture stirred at r.t. for 10 minutes. The solvent wasevaporated in vacuo. The crude product was purified by preparativereversed-phase HPLC and desired fractions were combined, and the solventevaporated in vacuo. The residue was dissolved in 1.1 MeCN—H₂O (2 mL)and the solution frozen. The solvent was then evaporated in vacuo(lyophilisation) to yield(3R)-1-hydroxy-7-((((R)-2-hydroxypropanoyl)oxy)methyl)-3-methyl-1,4,10-trioxo-2,5,9,11-tetraoxatridecan-12-yl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(3.5 mg, 33%) as a white solid. LCMS (Method F): Rt=7.31 min;[M+H]+=935.7. ¹H-NMR (400 MHz CDCl₃) δ 7.90-7.91 (1H, m), 7.81-7.85 (1H,m), 7.72 (1H, m), 7.61-7.67 (3H, m), 7.44-7.55 (1H, m), 7.32 (1H, d,J=7.8 Hz), 7.13 (1H, br s), 6.74-6.83 (2.5H, m), 6.64 (0.5H, d, J=8.2Hz), 5.26-5.32 (1H, m), 4.77 (2H, br s), 4.36-4.46 (1H, m), 4.12-4.32(7H, m), 3.78 (2H, m), 3.44-3.51 (1H, m), 3.26 (1H, dt, J=14.3, 7.6 Hz),3.05 (3H, d, J=1.4 Hz), 2.70-2.96 (4H, br m), 2.48-2.55 (1H, m), 1.57(3H, t, J=5.5 Hz, partially obscured by H₂O peak), 1.37-1.41 (6H, m).

Chemical Synthesis Example 19 1-Chloroethyl5-((R)-1,2-dithiolan-3-yl)pentanoate

To a stirred mixture of sodium bicarbonate (122 mg, 1.60 mmol),tetrabutylammonium hydrogen sulfate (14 mg, 0.0400 mmol), and lipoicacid (83 mg, 0.400 mmol) in DCM (3 mL) under an atmosphere of N₂ wasadded H₂O (3 mL) followed by a solution of 1-chloroethyl sulfochloridate(100 mg, 0.560 mmol) in DCM (1 mL). The reaction mixture was stirred atr.t. for 16 hours. The organic phase was separated (phase separator) andthe solvent evaporated in vacuo to yield 1-chloroethyl5-((R)-1,2-dithiolan-3-yl)pentanoate as a pale-yellow gum (130 mg) whichwas purified no further.

Chemical Synthesis Example 201-(((S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethyl5-((R)-1,2-dithiolan-3-yl)pentanoate

Crude 1-chloroethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate (74 mg, 0.275mmol) was dissolved in DMF (2.5 mL). Lifitegrast (178 mg, 0.275 mmol)and DIPEA (96 mL, 0.549 mmol) were added and the mixture stirred at 60°C. for 16 hours. The crude product was purified by preparativereversed-phase HPLC and desired fractions combined and the solventvolume reduced to 40 mL. The mixture was diluted with MeCN to produce ahomogeneous mixture. The solution was frozen and the solvent evaporatedin vacuo (lyophilisation) to yield1-(((S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethyl5-((R)-1,2-dithiolan-3-yl)pentanoate (9.1 mg, 4%) as a white solid. LCMS(Method C): Rt=7.97 min; [M+H]+=847.1. ¹H-NMR (400 MHz, CDCl₃) δ7.81-7.89 (2H, m), 7.71-7.72 (1H, m), 7.57-7.65 (3H, m), 7.47-7.52 (1H,m), 7.28-7.31 (1H, m), 6.88 (1H, td, J=10.8, 5.3 Hz), 6.81 (1H, m), 6.27(1H, dd, J=10.8, 8.0 Hz), 5.19-5.27 (1H, m), 4.75 (1H, br s), 3.81 (1H,br s), 3.39-3.58 (2H, m), 3.05-3.29 (3H, m), 3.03 (3H, d, J=4.1 Hz),2.87 (2H, br s), 2.31-2.48 (3H, m), 1.82-1.92 (1H, m), 1.38-1.74 (11H,m).

Chemical Synthesis Example 21 Methyl (R)-2-(trityloxy)propanoate

To a stirred solution of methyl (R)-2-hydroxypropanoate (0.91 mL, 11.1mmol), 4-(dimethylamino)pyridine (210 mg, 1.74 mmol) and pyridine (0.70mL) in MeCN (12 mL) was added triphenylmethyl chloride (2.38 g, 8.55mmol) and the mixture stirred at reflux for 16 hours. The reactionmixture was cooled and allowed to stand at r.t. for 24 hours thenpartitioned between EtOAc and H₂O. The organic phase was washedsuccessively with 1M NaHCO_(3(aq)), sat. NaHCO_(3(aq)), sat.Na₂CO_(3(aq)) and sat. brine solution. The organic phase was dried(MgSO₄), filtered and the solvent evaporated in vacuo to yield methyl(R)-2-(trityloxy)propanoate (2.98 g, 77%) as a pale yellow oil. ¹H-NMR(400 MHz, CDCl₃) δ 7.41-7.52 (6H, m), 7.18-7.35 (13H, m), 4.20 (1H, q,J=6.7 Hz), 3.22 (3H, s), 1.37 (3H, d, J=6.9 Hz).

Chemical Synthesis Example 22 (R)-2-(Trityloxy)propanoic Acid

Methyl (2R)-2-trityloxypropanoate (2.98 g, 8.60 mmol) and sodiumhydroxide (3.08 g, 77.0 mmol) were dissolved in MeOH (28 mL) and themixture stirred at r.t. for 72 hours. The reaction mixture was filtered,and the filtrate diluted with H₂O (40 mL). The MeOH was evaporated invacuo and the solution washed with tert-butyl methyl ether. The aqueousphase was acidified to pH3 by the addition of 5M HCl_((aq)) andextracted with tert-butyl methyl ether. The organic phase was washedwith sat. brine solution, dried (MgSO₄), and the solution filtered. Thesolvent was evaporated in vacuo to yield (R)-2-(trityloxy)propanoic acid(1.53 g, 54%) as a pale yellow gum. LCMS (Method E): Rt=2.87 min,[M−H]−=331.2.

Chemical Synthesis Example 23 1-Chloroethyl (2R)-2-(trityloxy)propanoate

To a stirred mixture of (R)-2-(trityloxy)propanoic acid (100 mg, 0.301mmol), tetrabutylammonium hydrogen sulfate (10 mg, 0.0301 mmol), andNaHCO₃ (101 mg, 1.20 mmol) in DCM (1.5 mL) and water (1.5 mL) under N₂was added 1-chloroethyl sulfochloridate (75 mg, 0.421 mmol) in DCM (0.5mL) and the mixture stirred at r.t. for 2 hours. The solution was passedthrough a phase separator, and the filtrate evaporated in vacuo to givecrude 1-chloroethyl (2R)-2-(trityloxy)propanoate (130 mg) as a paleyellow solid. LCMS (Method E): Rt=3.53 min (no ionisation).

Chemical Synthesis Example 24 1-(((R)-2-(Trityloxy)propanoyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

To a stirred solution of 1-chloroethyl (2R)-2-(trityloxy)propanoate (100mg, 0.253 mmol) in anhydrous DMF (2 mL) was added DIPEA (88 mL, 0.506mmol) and Lifitegrast (125 mg, 0.193 mmol) and the mixture stirred at55° C. under N₂ for 16 h. The mixture was diluted with EtOAc (50 mL) andsat. NaHCO_(3(aq)) (20 mL) and the layers separated. The organic phasewas washed with sat. brine solution (20 mL), dried (MgSO₄), filtered andthe solvent evaporated in vacuo. The crude product was purified by flashcolumn chromatography (Biotage SP1; 10 g cartridge) eluting withisohexane→EtOAc to yield 1-(((R)-2-(trityloxy)propanoyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(61 mg, 25%) as a white solid. LCMS (Method E): Rt=3.37 min;[M+H]+=973.2 (weak ionisation).

Chemical Synthesis Example 25 1-(((R)-2-Hydroxypropanoyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Method A

To a stirred solution of 1-(((R)-2-(trityloxy)propanoyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(14 mg, 0.0144 mmol) in anhydrous DCM (0.5 mL) at r.t. under N₂ wasadded triethylsilane (110 μL, 0.0719 mmol) followed by the dropwiseaddition of TFA (50 μL). The reaction was stirred at r.t. for 73 hours.Anhydrous DCM (1 mL), triethylsilane (110 μL, 0.0719 mmol) and TFA (50μL) were added and the reaction stirred at r.t. for 1 hour.

Method B

To a stirred solution of 1-(((R)-2-(trityloxy)propanoyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(48 mg, 0.0493 mmol) in anhydrous DCM (1.5 mL) at r.t. under N₂ wasadded triethylsilane (79 μL, 0.493 mmol) followed by the dropwiseaddition of TFA (150 μL). The mixture was stirred at r.t. for 75minutes.

Method C

The two reaction mixtures obtained from methods A & B were combined,diluted with DCM (30 mL) and sat. NaHCO_(3(aq)) (30 mL) and the layersseparated. The aqueous phase was extracted with DCM (20 mL) and thecombined organics washed with sat. brine solution (10 mL), dried(MgSO₄), filtered and the solvent evaporated in vacuo. The crude productwas purified by preparative reversed-phase HPLC. Desired fractions werecombined and the solution frozen. The solvent was evaporated in vacuo(lyophilisation) and the residue dissolved in 1:1 MeCN—H₂O, frozen, andevaporated in vacuo (lyophilisation) to yield1-(((R)-2-hydroxypropanoyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(15 mg, 42%) as a white solid. LCMS (Method C): Rt=6.49 min;[M+H]+=731.2. ¹H-NMR (400 MHz, CDCl₃) δ 7.79-7.88 (2H, m), 7.72 (1H, d,J=2.3 Hz), 7.57-7.68 (3H, m), 7.51 (1H, td, J=7.9, 3.5 Hz), 7.31 (1H, d,J=7.8 Hz), 6.90-6.98 (1H, m), 6.80-6.86 (1H, m), 6.22-6.40 (1H, m), 5.24(1H, dd, J=14.0, 6.2 Hz), 4.79 (2H, s), 4.24-4.37 (1H, m), 3.87 (2H, brs), 3.38-3.44 (1H, m), 3.21-3.32 (1H, m), 3.06 (3H, d, J=10.5 Hz), 2.88(2H, s), 1.55 (3H, dd, J=12.4, 5.5 Hz), 1.42 (3H, dd, J=7.1, 5.7 Hz).

Chemical Synthesis Example 26

The following compound was made by analogous method to that describedabove for 1-(((R)-2-Hydroxypropanoyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate:

Structure Analytical Data

LCMS (QC Method C): Rt = 6.34 mins; [M + H]+ = 717.0

Chemical Synthesis Example 271-(((S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethylpivalate

To a stirred solution of 1-chloroethyl pivalate (40 mg, 0.243 mmol) inanhydrous DMF (1.6 mL) was added DIPEA (85 mL, 0.486 mmol) andLifitegrast (130 mg, 0.201 mmol). The mixture was stirred at 40° C.under N₂ for 72 h. The crude product was purified by preparativereversed-phase HPLC, desired fractions were combined and approximatelyhalf the solvent evaporated in vacuo. The solution was frozen and thesolvent evaporated in vacuo (lyophilisation) to yield1-(((S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoyl)oxy)ethylpivalate (40 mg, 22%) as an off-white solid. LCMS (Method C): Rt=7.66min; [M+H]+=743.1. ¹H-NMR (400 MHz, CDCl₃) δ 7.80-7.91 (2H, m), 7.71(1H, d, J=1.8 Hz), 7.56-7.64 (3H, m), 7.49 (1H, td, J=7.7, 5.3 Hz), 7.29(1H, d, J=6.4 Hz), 6.81-6.89 (2H, m), 6.32 (1H, q, J=7.8 Hz), 5.19-5.27(1H, m), 4.74 (2H, br s), 3.78 (2H, br s), 3.41 (1H, dd, J=14.4, 5.7Hz), 3.11-3.27 (1H, m), 3.03 (3H, d, J=6.9 Hz), 2.85-2.94 (2H, m), 1.50(3H, dd, J=15.8, 5.3 Hz), 1.15-1.19 (9H, m).

Chemical Synthesis Example 28 1-((Methoxycarbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

Lifitegrast (205 mg, 0.333 mmol) and DIPEA (90 mL, 0.517 mmol) weredissolved in anhydrous DMF (5 mL). 1-Chloroethyl methyl carbonate (40mg, 0.289 mmol) was added and the mixture stirred at r.t. for 16 hoursfollowed by stirring at 40° C. for 2 hours. DIPEA (50 mL, 0.287 mmol)was added and the mixture stirred at 50° C. for 20 hours. The solventwas evaporated in vacuo and the residue dissolved in DCM (20 mL). Thesolution was washed with sat. NaHCO_(3(aq)) (20 mL) and the layersseparated. The organic phase was evaporated in vacuo and the crudeproduct purified by flash chromatography eluting with isohexane→8:2EtOAc-isohexane to yield 1-((methoxycarbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(88 mg, 42%) as a white solid. LCMS (Method C): Rt=6.94 min;[M+H]+=717.1. ¹H-NMR (400 MHz, CDCl₃) δ 7.79-7.86 (2H, m), 7.70 (1H, d,J=1.8 Hz), 7.57-7.64 (3H, m), 7.45-7.51 (1H, m), 7.28 (1H, d, J=7.8 Hz),6.75-6.80 (2H, m), 6.43 (1H, t, J=8.5 Hz), 5.24 (1H, s), 4.72 (2H, brs), 3.59-4.00 (5H, m), 3.41 (1H, dd, J=14.7, 5.5 Hz), 3.21-3.29 (1H, m),3.01 (3H, d, J=3.7 Hz), 2.85 (2H, s), 1.51-1.64 (4H, m).

Chemical Synthesis Example 29 1-((Ethoxycarbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

To a stirred solution of 1-chloroethyl ethyl carbonate (37 mg, 0.243mmol) in DMF (1.6 mL) was added DIPEA (85 mL, 0.486 mmol) andLifitegrast (120 mg, 0.185 mmol) and the mixture stirred at 40° C. underN₂ for 16 hours. DIPEA (85 mL, 0.486 mmol) and 1-chloroethyl ethylcarbonate (37 mg, 0.243 mmol) were added and the mixture stirred at 40°C. for 4 hours. The crude product was purified by preparativereversed-phase HPLC. Fractions containing desired product were combined,frozen and the solvent evaporated in vacuo (lyophilisation) to yield1-((ethoxycarbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(6.0 mg, 3%) as an off-white solid. LCMS (Method C): Rt=7.15 min;[M+H]+=731.1.

Chemical Synthesis Example 30 1-Chloroethyl Propionate

Propionyl chloride (7.0 mL, 80.1 mmol) was placed under an atmosphere ofN₂ and cooled to 0° C. Zinc chloride (0.7M in THF, 1.10 mL, 0.801 mmol)was added followed by chilled acetaldehyde (5.40 mL, 96.1 mmol). Thereaction mixture was stirred at 0° C. for 2 hours. The mixture wasfiltered and the filtrate evaporated in vacuo. The residue was dissolvedin isohexane (10 mL) and the solution washed successively with sat.NaHCO_(3(aq)) (10 mL), H₂O (10 mL) and sat. brine solution (10 mL). Theorganic phase was dried (MgSO₄), filtered and the solvent evaporated invacuo to yield 1-chloroethyl propionate (4.54 g, 41%) as an orange oil*.

*The product contained a mixture of impurities and was purified nofurther—used subsequently in crude form.

Chemical Synthesis Example 31 1-((Ethoxycarbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate

A mixture of Lifitegrast (100 mg, 0.162 mmol) and 1-chloroethylpropionate (111 mg, 0.812 mmol) were dissolved in DMF (1 mL). DIPEA (170mL, 0.975 mmol) was added and the mixture stirred at 60° C. under N₂ for18 hours. The crude product was purified by preparative reversed-phaseHPLC and desired fractions combined, frozen and the solvent evaporatedin vacuo (lyophilisation) to yield 1-((ethoxycarbonyl)oxy)ethyl(2S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate(41.1 mg, 35%) as an off-white solid. LCMS (Method B): Rt=3.08 min;[M+H]+=715.3. ¹H-NMR (400 MHz, CDCl₃) δ 7.83-7.90 (2H, m), 7.73 (1H, d,J=2.7 Hz), 7.65 (1H, d, J=7.8 Hz), 7.59-7.61 (2H, m), 7.48-7.53 (1H, m),7.31-7.33 (1H, m), 7.14 (1H, br s), 6.87-6.93 (1H, m), 6.82-6.83 (1H,m), 6.22-6.28 (1H, m), 5.21-5.28 (1H, m), 4.78 (2H, br s), 3.84 (2H, brs), 3.40-3.46 (1H, m), 3.20-3.31 (1H, m), 3.05 (1.5H, s), 3.04 (1.5H, s)2.88 (2H, br s), 2.32-2.41 (2H, m), 1.53 (1.5H, d, J=5.2 Hz, partiallyobscured by H₂O peak), 1.50 (1.5H, d, J=5.6 Hz), 1.11-1.17 (3H, m).

II. Biological Evaluation Example 1: Rabbit Cornea Homogenate StabilityAssay

Determining Rabbit Cornea Homogenate stability of the test compounds wasperformed using HPLC-MS. The assay was performed at two concentrationsof Rabbit Cornea Homogenate (0.15 mg/ml and 0.45 mg/ml total protein) sothat any hydrolysis observed could be assigned as esterase dependent ornot.

Rabbit Cornea Homogenisation

Five rabbit corneas (e.g. New Zealand Whites) of approx. 50 mg each weresliced and scraped with a scalpel and tweezers until reduced to small(1-3 mm), thin pieces. These were transferred into a tared vial andaccurately weighed, then diluted with 10 volumes aqueous PBS pH7.4

Sample was cooled intermittently on ice and shear homogenized for 3minutes, then centrifuged for 3 min at 3000 rpm. The supernatant waspipetted off into a vial, and total protein concentration determined at280 nm. Sample was stored at −78° C.

Rabbit Cornea Esterase Assay Preparation of Stock Solutions:

10 mM Compound stocks were diluted to 100 μM in a 96 deep-well plate: 10μl of 10 mM Compound stock was added to 990 μl 50 mM HEPES, pH7.5buffer.

Compounds were further diluted to 10 μM: 100 μl of 100 μM compound wasadded to 900 μl 50 mM HEPES, pH7.5 buffer.Esterase homogenate was diluted to 300 ng/μl and 900 ng/μl

Assay Conditions:

A heater shaker was set to 37° C. Into a suitable 96 well plate (RunPlate), 75 μl of 300 or 900 ng/μl esterase homogenate was pipetted intoeach of the required wells (2 min, 5 min, 10 min, 20 min and 45 min).The plate was sealed and then warmed at 37° C. for 5 min.Another 96 well PCR plate is put on ice (Kill Plate). To this was added100 μl of MeCN to each well, labelled 0 min, 2 min, 5 min, 10 min, 20min and 45 min. The plate was covered to minimise evaporation.For the T=0 sample only, to the 100 μl cold MeCN stop solution was added50 μl of 300 or 900 ng/μl esterase homogenate followed by 50 μl of 10 μMcompound solutionFor the remaining time points, 75 μl of 10 μM compound solution wasadded to the Run Plate starting from T=45 min row and ending with T=2min row.At the appropriate time point, 100 μl of the assay mixture was added tothe matching kill plate well containing 100 μl of cold MeCN.Samples were analysed as soon as practicable by LCMS (Waters Xevo TQ-Sor Micromass Ultima).

Parent conjugate and parent concentrations were determined againstappropriate standard response curves and the half-life (T_(1/2)) of theparent conjugate was calculated using the peak area of the parentconjugate at each time point in the linear region of the log—linearplot.

Hydrolysis Rates of Example Compounds

TABLE 2 Cornea Esterase % API Homogenate Lifitegrast Formation Concformation at rate Comp (mg/mL) 45 min (%/min) 2 0.15 B b 0.45 C c 3 0.15B d 0.45 C b 4 0.15 B b 0.45 C c 5 0.15 B b 0.45 D d 6 0.15 A a 0.45 B b7 0.15 B b 0.45 C c 8 0.15 B b 0.45 C d 9 0.15 B b 0.45 C d 10 0.15 A b0.45 B b 11 0.15 B b 0.45 B c 12 0.15 A a 0.45 A a 13 0.15 A a 0.45 A a14 0.15 C c 0.45 D d 15 0.15 C d 0.45 D d 16 0.15 D d 0.45 D d 17 0.15 Bb 0.45 C c 18 0.15 C c 0.45 D d 19 0.15 B b 0.45 B b 20 0.15 A a 0.45 Bb A: percent active pharmaceutical ingredient (API) formation <25%; B:percent API formation 25% to 50%; C: percent API formation 51% to 75%;D: percent API formation >75%. a: API formation rate <0.5%/min; b: APIformation rate 0.5-1.0%/min; c: API formation rate 1.0-1.5%/min; APIformation rate >1.5%/min.

Example 2: Aqueous Hydrolysis Stability Assay

Determination of aqueous stability of the test compounds was performedusing HIPLC-MS. A test compound 10 mM stock solution was prepared inDMSO. 10 μl of the DMSO stock solution was dissolved in 990 μl of 50 mMHEPES pH 7.5 buffer or 1:1 (v/v) of Acetonitrile:Water to make a100 μMsolution. Final DMSO concentration was 1%. The solution was kept at roomtemperature and injected without delay into the LCMS (Waters Xevo TQ-Sor Micromass Ultima). Additional injections were performed atappropriate time points. Half-life (T_(1/2)) of the parent conjugate wascalculated using the peak area of the parent conjugate at each timepoint in the linear region of the log—linear plot.

TABLE 3 Hydrolytic % Lifitegrast Comp formation at [time] 2 A [192 min]3 B [45 min] 4 B [45 min] 5 A [192 min] 6 C [142 min] 7 B [142 min] 8 A[45 min] 9 B [142 min] 10 C [142 min] 11 C [142 min] 12 B [142 min] 13 —14 B [142 min] 15 B [45 min] 16 C [142 min] 17 A [45 min] 18 C [45 min]19 B [45 min] 20 A [45 min] A: percent active pharmaceutical ingredient(API) formation <1.5%; B: percent API formation 1.5-4%; C: percent APIformation >4%.

Example 3: Mouse Model of Experimental Dry Eye Disease

Female C57BL/6 mice (6-8 weeks old) or female HEL BCR Tg mice (6-8 weeksold) are commercially obtained. Experimental dry eye is induced asdescribed by Niederkorn, et al. (J. Immunol. 2006,176:3950-3957) andDursun et al. (Invest. Ophthalmol. Vis. Sci. 2002, 43:632-638). Inbrief, mice are exposed to desiccating stress in perforated cages withconstant airflow from fans positioned on both sides and room humiditymaintained at 30% to 35%. Injection of scopolamine hydrobromide (0.5mg/0.2 mL; Sigma-Aldrich, St. Louis, Mo.) is administeredsubcutaneously, three times a day (8:00 AM, 12:00 noon, and 5:00 PM), onalternating hind-flanks to augment disease. Mice are exposed todesiccating stress for 3 weeks. Untreated control mice are maintained ina nonstressed environment at 50% to 75% relative humidity withoutexposure to forced air. Test animals are exposed to test compound andsubsequently tear samples are obtained to determine stability of testcompounds, and tissue samples are taken to determine presence ofpro-inflammatory biomarkers.

III. Preparation of Pharmaceutical Dosage Forms Example 1: Solution forTopical Ophthalmic Use

The active ingredient is a compound of Table 1, or a pharmaceuticallyacceptable salt thereof, and is formulated as a solution with aconcentration of between 0.1-1.5% w/v.

We claim:
 1. A compound, having the structure of Formula (III):

X is a bond or —O—; R⁸ is hydrogen or optionally substituted alkyl; R⁹is optionally substituted alkyl or optionally substituted heteroalkyl,or a pharmaceutically acceptable salt or solvate thereof.
 2. Thecompound of claim 1, wherein R⁸ is C₁-C₄ alkyl.
 3. The compound of claim1, wherein R⁸ is methyl.
 4. The compound of claim 1, wherein X is abond.
 5. The compound of claim 1, wherein R⁹ is optionally substitutedC₁-C₆ alkyl.
 6. The compound of claim 5, wherein R⁹ is unsubstitutedC₁-C₆ alkyl.
 7. The compound of claim 5, wherein the C₁-C₆ alkyl issubstituted with one or more substituents, each substituent beingindependently selected from the group consisting of alkyl, heteroalkyl,hydroxyl, thiol, amide, ester, and heterocycloalkyl, wherein the alkyl,heteroalkyl, and heterocycloalkyl are each independently furtheroptionally substituted.
 8. The compound of claim 7, wherein the C₁-C₆alkyl is substituted with one or more substituent(s), each substituentbeing independently selected from the group consisting of —OH, alkyl,and heterocycloalkyl.
 9. The compound of claim 8, wherein R⁹ is C₁-C₄alkyl, —CH(CH₃)OH, —CH₂OH, or


10. The compound of claim 1, wherein X is —O—.
 11. The compound of claim1, wherein R⁹ is optionally substituted C₁-C₆ alkyl.
 12. The compound ofclaim 11, wherein R⁹ is unsubstituted C₁-C₆ alkyl.
 13. The compound ofclaim 11, wherein the C₁-C₆ alkyl is substituted with one or moresubstituents, each substituent being independently selected from thegroup consisting of alkyl, heteroalkyl, hydroxyl, ester, andheterocycloalkyl, wherein the alkyl, heteroalkyl, ester, andheterocycloalkyl are each independently further optionally substituted.14. The compound of claim 13, wherein the C₁-C₆ alkyl is substitutedwith one or more substituent(s), each substituent being independentlyselected from the group consisting of —OH and alkyl, the alkyl beingoptionally substituted with alkyl or optionally substitutedheterocycloalkyl.
 15. The compound of claim 13, wherein the ester isfurther substituted with alkyl, wherein the alkyl is further optionallysubstituted with one or more substituent(s), each substituent beingindependently selected from the group consisting of —OH and alkyl. 16.The compound of claim 13, wherein R⁹ is C₁-C₄ alkyl,


17. The compound of claim 16, wherein the C₁-C₄ alkyl is methyl, ethyl,propyl, isopropyl, or tert-butyl.
 18. The compound of claim 1 selectedfrom the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.
 19. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.
 20. A method of treating a dermalor an ophthalmic disease or disorder in an individual in need ofthereof, comprising administering to the individual a compositioncomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof.